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Curry JN, McCormick JA. Stuck in Traffic-Myosin Motors Ease Gridlock in the Loop. FUNCTION 2025; 6:zqaf008. [PMID: 39986266 PMCID: PMC11903388 DOI: 10.1093/function/zqaf008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Accepted: 02/19/2025] [Indexed: 02/24/2025] Open
Affiliation(s)
- Joshua N Curry
- Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, OR 97239, USA
| | - James A McCormick
- Division of Nephrology and Hypertension, Oregon Health and Science University, Portland, OR 97239, USA
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2
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Horibe Y, Yamanaka K, Kaimori J, Miyata Y, Fukae S, Yoshida T, Nakagawa M, Ishihara Y, Nagata M, Miyashita Y, Asano Y, Kishikawa H. MYH9-related disorder with sole presentation of end-stage kidney disease and long-term, recurrence-free living after living donor renal transplantation: a case report. CEN Case Rep 2025; 14:11-15. [PMID: 38831180 PMCID: PMC11785911 DOI: 10.1007/s13730-024-00892-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 05/10/2024] [Indexed: 06/05/2024] Open
Abstract
MYH9-related disorders are a group of autosomal dominant disorders caused by mutations in MYH9, and are characterized by thrombocytopenia, sensorineural hearing loss, cataracts, and renal failure. Here, we report a case of chronic renal failure due to MYH9-related disorder with renal symptoms in a patient who underwent living-donor renal transplantation. The patient was diagnosed with proteinuria during a health checkup at the age of 12 years. Her renal function gradually deteriorated, and hemodialysis was initiated at 34 years of age. No definitive diagnosis of renal disease was made through renal biopsy. At the age of 35, she underwent living-donor renal transplantation from her mother as the donor. Six years after transplantation, her renal function remained stable, and no evidence of recurrent nephritis was found during renal biopsies. The family history revealed that her father, uncle, and younger brother had end-stage kidney disease. Genetic testing revealed a mutation (p.E1653D) related to the MYH9 gene. As her father had a history of renal biopsy and was diagnosed with focal segmental glomerulosclerosis (FSGS), we diagnosed chronic renal failure due to FSGS associated with MYH9 disorder. There were no findings suggestive of hearing loss, cataracts, or thrombocytopenia in the recipient or their family members with renal failure, and no symptoms other than renal failure were noted.
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Affiliation(s)
- Yuki Horibe
- Department of Urology, Hyogo Prefectural Nishinomiya Hospital, 13-9 Rokutanjicho, Nishinomiya, Hyogo, 662-0918, Japan
| | - Kazuaki Yamanaka
- Department of Urology, Hyogo Prefectural Nishinomiya Hospital, 13-9 Rokutanjicho, Nishinomiya, Hyogo, 662-0918, Japan.
| | - Junya Kaimori
- Department of Nephrology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yuji Miyata
- Department of Urology, Hyogo Prefectural Nishinomiya Hospital, 13-9 Rokutanjicho, Nishinomiya, Hyogo, 662-0918, Japan
| | - Shota Fukae
- Department of Urology, Hyogo Prefectural Nishinomiya Hospital, 13-9 Rokutanjicho, Nishinomiya, Hyogo, 662-0918, Japan
| | - Takahiro Yoshida
- Department of Urology, Hyogo Prefectural Nishinomiya Hospital, 13-9 Rokutanjicho, Nishinomiya, Hyogo, 662-0918, Japan
| | - Masahiro Nakagawa
- Department of Urology, Hyogo Prefectural Nishinomiya Hospital, 13-9 Rokutanjicho, Nishinomiya, Hyogo, 662-0918, Japan
| | - Yasuki Ishihara
- Department of Cardiology Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Miho Nagata
- Department of Cardiology Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yohei Miyashita
- Department of Legal Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Yoshihiro Asano
- Department of Cardiology Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan
| | - Hidefumi Kishikawa
- Department of Urology, Hyogo Prefectural Nishinomiya Hospital, 13-9 Rokutanjicho, Nishinomiya, Hyogo, 662-0918, Japan
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Han S, Oh D, Vanderheijden N, Xie J, Balmelle N, Tignon M, Nauwynck HJ. Monoclonal Antibodies Targeting Porcine Macrophages Are Able to Inhibit the Cell Entry of Macrophage-Tropic Viruses (PRRSV and ASFV). Viruses 2025; 17:167. [PMID: 40006922 PMCID: PMC11860747 DOI: 10.3390/v17020167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/19/2025] [Accepted: 01/23/2025] [Indexed: 02/27/2025] Open
Abstract
Porcine reproductive and respiratory syndrome virus (PRRSV) and African swine fever virus (ASFV) cause serious economic losses to the swine industry worldwide. Both viruses show a tropism for macrophages, based on the use of specific entry mediators (e.g., Siglec-1 and CD163). Identifying additional mediators of viral entry is essential for advancing antiviral and vaccine development. In this context, monoclonal antibodies (mAbs) are valuable tools. This study employed a library of 166 mAbs targeting porcine alveolar macrophages (PAMs) to identify candidates capable of blocking early infection stages, including viral binding, internalization, and fusion. Immunofluorescence analysis revealed 74 mAbs with cytoplasmic staining and 70 mAbs with membrane staining. Fifteen reacted with blood monocytes as determined by flow cytometry. mAb blocking assays were performed at 4 °C and 37 °C to analyze the ability of mAbs to block PRRSV and/or ASFV infections in PAMs. The mAb 28C10 significantly blocked PRRSV (96% at 4 °C and 80% at 37 °C) and ASFV (64% at 4 °C and 81% at 37 °C) infections. The mAb 28G10B6 significantly blocked PRRSV (86% at 4 °C and 74% at 37 °C) and partially blocked ASFV (35% at 4 °C and 64% at 37 °C) infections. mAb 26B8F5-I only partially blocked PRRSV infection (65% at 4 °C and 46% at 37 °C). Western blotting and mass spectrometry identified the corresponding proteins as Siglec-1 (28C10; 250 kDa), MYH9 (28G10B6; 260 kDa), and ANXA1 (26B8F5-I; 37 kDa). Our findings are indicative that Siglec-1, MYH9, and ANXA1 play a role in PRRSV/ASFV entry into macrophages.
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Affiliation(s)
- Shaojie Han
- Laboratory of Virology, Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
| | - Dayoung Oh
- Laboratory of Virology, Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
| | - Nathalie Vanderheijden
- Laboratory of Virology, Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
| | - Jiexiong Xie
- Laboratory of Virology, Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
| | - Nadège Balmelle
- Service Viral Re-Emerging, Enzootic and Bee Diseases, Department Infectious Diseases in Animals, Sciensano, Groeselenbergstraat 99, 1180 Brussels, Belgium
| | - Marylène Tignon
- Service Viral Re-Emerging, Enzootic and Bee Diseases, Department Infectious Diseases in Animals, Sciensano, Groeselenbergstraat 99, 1180 Brussels, Belgium
| | - Hans J. Nauwynck
- Laboratory of Virology, Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, 9820 Merelbeke, Belgium
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Sato D, Kirikae H, Nakano T, Katayama S, Yaoita H, Takayama J, Tamiya G, Kure S, Kikuchi A, Sasahara Y. Comprehensive genetic analysis for identification of monogenic disorders and selection of appropriate treatments in pediatric patients with persistent thrombocytopenia. Pediatr Hematol Oncol 2024; 41:541-556. [PMID: 39318204 DOI: 10.1080/08880018.2024.2395358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2024] [Revised: 07/27/2024] [Accepted: 08/18/2024] [Indexed: 09/26/2024]
Abstract
Persistent thrombocytopenia is caused by various diseases, including immune thrombocytopenia, inherited thrombocytopenia, and inherited bone marrow failure syndromes. Considering the large number of genes responsible for inherited disorders, comprehensive genetic analysis is required to diagnose monogenic disorders. In this study, we enrolled 53 pediatric patients with persistent thrombocytopenia exhibiting visually small or normal-sized platelets. We performed whole-exome sequencing, including 56 genes responsible for inherited thrombocytopenia, and evaluated clinical parameters according to disease type. Among 53 patients, 12 patients (22.6%) were diagnosed with monogenic disorders. Nine patients had a family history of thrombocytopenia. Pathogenic or novel variants of genes responsible for inherited thrombocytopenia were identified in three and six patients, respectively. The variants in genes for inherited thrombocytopenia with large or giant platelets were unexpectedly identified in six patients. Pathogenic variants in genes for inherited bone marrow failure syndromes with systemic features were identified in three patients with atypical symptoms. Since the definitive diagnostic methods for immune thrombocytopenia are limited, and a substantial number of patients with inherited thrombocytopenia are at a high risk of developing malignancies, comprehensive genetic analysis is indispensable for selecting appropriate therapies, avoidance of unnecessary treatments for immune thrombocytopenia, and long-term follow-up of patients with inherited thrombocytopenia.
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Affiliation(s)
- Daichi Sato
- Department of Pediatrics, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Hinako Kirikae
- Department of Pediatrics, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Tomohiro Nakano
- Department of Pediatrics, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Saori Katayama
- Department of Pediatrics, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Hisao Yaoita
- Department of Pediatrics, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Jun Takayama
- Department of Rare Disease Genomics, Tohoku University Graduate School of Medicine, Miyagi, Japan
- Department of AI and Innovative Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan
- Statistical Genetics Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
| | - Gen Tamiya
- Department of Rare Disease Genomics, Tohoku University Graduate School of Medicine, Miyagi, Japan
- Department of AI and Innovative Medicine, Tohoku University Graduate School of Medicine, Miyagi, Japan
- Statistical Genetics Team, RIKEN Center for Advanced Intelligence Project, Tokyo, Japan
| | - Shigeo Kure
- Department of Pediatrics, Tohoku University Graduate School of Medicine, Miyagi, Japan
- Department of Rare Disease Genomics, Tohoku University Graduate School of Medicine, Miyagi, Japan
- Miyagi Children's Hospital, Miyagi, Japan
| | - Atsuo Kikuchi
- Department of Pediatrics, Tohoku University Graduate School of Medicine, Miyagi, Japan
- Department of Rare Disease Genomics, Tohoku University Graduate School of Medicine, Miyagi, Japan
| | - Yoji Sasahara
- Department of Pediatrics, Tohoku University Graduate School of Medicine, Miyagi, Japan
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5
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Costacurta M, Sandow JJ, Maher B, Susanto O, Vervoort SJ, Devlin JR, Garama D, Condina MR, Steele JR, Kahrood HV, Gough D, Johnstone RW, Shortt J. Mapping the IMiD-dependent cereblon interactome using BioID-proximity labelling. FEBS J 2024; 291:4892-4912. [PMID: 38975872 DOI: 10.1111/febs.17196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 04/17/2024] [Accepted: 05/24/2024] [Indexed: 07/09/2024]
Abstract
Immunomodulatory imide drugs (IMiDs) are central components of therapy for multiple myeloma (MM). IMiDs bind cereblon (CRBN), an adaptor for the CUL4-DDB1-RBX1 E3 ligase to change its substrate specificity and induce degradation of 'neosubstrate' transcription factors that are essential to MM cells. Mechanistic studies to date have largely focussed on mediators of therapeutic activity and insight into clinical IMiD toxicities is less developed. We adopted BioID2-dependent proximity labelling (BioID2-CRBN) to characterise the CRBN interactome in the presence and absence of various IMiDs and the proteasome inhibitor, bortezomib. We aimed to leverage this technology to further map CRBN interactions beyond what has been achieved by conventional proteomic techniques. In support of this approach, analysis of cells expressing BioID2-CRBN following IMiD treatment displayed biotinylation of known CRBN interactors and neosubstrates. We observed that bortezomib alone significantly modifies the CRBN interactome. Proximity labelling also suggested that IMiDs augment the interaction between CRBN and proteins that are not degraded, thus designating 'neointeractors' distinct from previously disclosed 'neosubstrates'. Here we identify Non-Muscle Myosin Heavy Chain IIA (MYH9) as a putative CRBN neointeractor that may contribute to the haematological toxicity of IMiDs. These studies provide proof of concept for proximity labelling technologies in the mechanistic profiling of IMiDs and related E3-ligase-modulating drugs.
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Affiliation(s)
- Matteo Costacurta
- Monash Haematology, Monash Health, Clayton, Australia
- Blood Cancer Therapeutics Laboratory, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia
| | - Jarrod J Sandow
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
| | - Belinda Maher
- Monash Haematology, Monash Health, Clayton, Australia
- Blood Cancer Therapeutics Laboratory, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia
| | - Olivia Susanto
- Monash Haematology, Monash Health, Clayton, Australia
- Blood Cancer Therapeutics Laboratory, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia
| | - Stephin J Vervoort
- The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia
| | - Jennifer R Devlin
- Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
| | - Daniel Garama
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Australia
- Department of Molecular and Translational Science, Monash University, Clayton, Australia
| | - Mark R Condina
- Mass Dynamics, Melbourne, Australia
- Clinical & Health Sciences, University of South Australia, Adelaide, Australia
| | - Joel R Steele
- Monash Proteomics and Metabolomics Platform, Monash Biomedicine Discovery Institute, Monash University, Clayton, Australia
- Monash Bioinformatics Platform, Monash Biomedicine Discovery Institute, Monash University, Clayton, Australia
| | - Hossein V Kahrood
- Monash Proteomics and Metabolomics Platform, Monash Biomedicine Discovery Institute, Monash University, Clayton, Australia
| | - Daniel Gough
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Australia
- Department of Molecular and Translational Science, Monash University, Clayton, Australia
| | - Ricky W Johnstone
- Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
| | - Jake Shortt
- Monash Haematology, Monash Health, Clayton, Australia
- Blood Cancer Therapeutics Laboratory, School of Clinical Sciences at Monash Health, Monash University, Clayton, Australia
- Translational Haematology Program, Peter MacCallum Cancer Centre, Melbourne, Australia
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia
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Cai L, Chen S, Zhou Y, Yu H, Li Y, Bao A, Zhang J, Lv Q. Unraveling MYH9-related disease: A case study on misdiagnosis with idiopathic thrombocytopenic purpura, confirmed through genetic. Heliyon 2024; 10:e36203. [PMID: 39309903 PMCID: PMC11415704 DOI: 10.1016/j.heliyon.2024.e36203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 08/12/2024] [Accepted: 08/12/2024] [Indexed: 09/25/2024] Open
Abstract
This paper presents a detailed analysis of a case initially misdiagnosed as Idiopathic Thrombocytopenic Purpura (ITP), which was later correctly identified as MYH9-related disease (MYH9-RD), a rare genetic disorder characterized by thrombocytopenia, large platelets, and Döhle-like inclusion bodies in neutrophils. Using advanced slide reading technology, our team identified hallmark features of MYH9-RD in the patient's blood samples, leading to genetic testing that confirmed a spontaneous mutation in the MYH9 gene. This report highlights the diagnostic journey, emphasizing the crucial role of recognizing specific hematologic signs to accurately diagnose MYH9-RD. By comparing our findings with existing literature, we highlight the genetic underpinnings and clinical manifestations of MYH9-RD, emphasizing the necessity for heightened awareness and diagnostic precision in clinical practice to prevent similar cases of misdiagnosis. This case demonstrates the importance of integrating genetic testing into routine diagnostic protocols for unexplained thrombocytopenia, paving the way for improved patient care and treatment outcomes.
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Affiliation(s)
- Lixiu Cai
- Department of Medical Laboratory, The First People's Hospital of Shuangliu, Chengdu/West China (Airport) Hospital Sichuan University, No.120, Chengbei Shangjie, Dongsheng Street, Shuangliu District, Chengdu, 610200, Sichuan Province, China
| | - Shuangyan Chen
- Department of Medical Laboratory, The First People's Hospital of Shuangliu, Chengdu/West China (Airport) Hospital Sichuan University, No.120, Chengbei Shangjie, Dongsheng Street, Shuangliu District, Chengdu, 610200, Sichuan Province, China
| | - Yu Zhou
- Department of Medical Laboratory, The First People's Hospital of Shuangliu, Chengdu/West China (Airport) Hospital Sichuan University, No.120, Chengbei Shangjie, Dongsheng Street, Shuangliu District, Chengdu, 610200, Sichuan Province, China
| | - Hao Yu
- Department of Medical Laboratory, The First People's Hospital of Shuangliu, Chengdu/West China (Airport) Hospital Sichuan University, No.120, Chengbei Shangjie, Dongsheng Street, Shuangliu District, Chengdu, 610200, Sichuan Province, China
| | - Ya Li
- Department of Medical Laboratory, The First People's Hospital of Shuangliu, Chengdu/West China (Airport) Hospital Sichuan University, No.120, Chengbei Shangjie, Dongsheng Street, Shuangliu District, Chengdu, 610200, Sichuan Province, China
| | - Aiping Bao
- Department of Medical Laboratory, The First People's Hospital of Shuangliu, Chengdu/West China (Airport) Hospital Sichuan University, No.120, Chengbei Shangjie, Dongsheng Street, Shuangliu District, Chengdu, 610200, Sichuan Province, China
| | - Jin Zhang
- Department of Medical Laboratory, The First People's Hospital of Shuangliu, Chengdu/West China (Airport) Hospital Sichuan University, No.120, Chengbei Shangjie, Dongsheng Street, Shuangliu District, Chengdu, 610200, Sichuan Province, China
| | - Qin Lv
- Department of Respiratory and Critical Care Medicine, Sichuan Provincial People's Hospital, No.32, West 2nd Section, 1st Ring Road, Qingyang District, Chengdu, 610072, Sichuan Province, China
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Feroz W, Park BS, Siripurapu M, Ntim N, Kilroy MK, Sheikh AMA, Mishra R, Garrett JT. Non-Muscle Myosin II A: Friend or Foe in Cancer? Int J Mol Sci 2024; 25:9435. [PMID: 39273383 PMCID: PMC11395477 DOI: 10.3390/ijms25179435] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2024] [Revised: 08/26/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024] Open
Abstract
Non-muscle myosin IIA (NM IIA) is a motor protein that belongs to the myosin II family. The myosin heavy chain 9 (MYH9) gene encodes the heavy chain of NM IIA. NM IIA is a hexamer and contains three pairs of peptides, which include the dimer of heavy chains, essential light chains, and regulatory light chains. NM IIA is a part of the actomyosin complex that generates mechanical force and tension to carry out essential cellular functions, including adhesion, cytokinesis, migration, and the maintenance of cell shape and polarity. These functions are regulated via light and heavy chain phosphorylation at different amino acid residues. Apart from physiological functions, NM IIA is also linked to the development of cancer and genetic and neurological disorders. MYH9 gene mutations result in the development of several autosomal dominant disorders, such as May-Hegglin anomaly (MHA) and Epstein syndrome (EPS). Multiple studies have reported NM IIA as a tumor suppressor in melanoma and head and neck squamous cell carcinoma; however, studies also indicate that NM IIA is a critical player in promoting tumorigenesis, chemoradiotherapy resistance, and stemness. The ROCK-NM IIA pathway regulates cellular movement and shape via the control of cytoskeletal dynamics. In addition, the ROCK-NM IIA pathway is dysregulated in various solid tumors and leukemia. Currently, there are very few compounds targeting NM IIA, and most of these compounds are still being studied in preclinical models. This review provides comprehensive evidence highlighting the dual role of NM IIA in multiple cancer types and summarizes the signaling networks involved in tumorigenesis. Furthermore, we also discuss the role of NM IIA as a potential therapeutic target with a focus on the ROCK-NM IIA pathway.
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Affiliation(s)
- Wasim Feroz
- Department of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, Cincinnati, OH 45229, USA; (W.F.); (B.S.P.); (M.S.); (N.N.); (M.K.K.); (R.M.)
| | - Briley SoYoung Park
- Department of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, Cincinnati, OH 45229, USA; (W.F.); (B.S.P.); (M.S.); (N.N.); (M.K.K.); (R.M.)
- Cancer Research Scholars Program, College of Allied Health Sciences, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Meghna Siripurapu
- Department of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, Cincinnati, OH 45229, USA; (W.F.); (B.S.P.); (M.S.); (N.N.); (M.K.K.); (R.M.)
| | - Nicole Ntim
- Department of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, Cincinnati, OH 45229, USA; (W.F.); (B.S.P.); (M.S.); (N.N.); (M.K.K.); (R.M.)
| | - Mary Kate Kilroy
- Department of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, Cincinnati, OH 45229, USA; (W.F.); (B.S.P.); (M.S.); (N.N.); (M.K.K.); (R.M.)
| | | | - Rosalin Mishra
- Department of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, Cincinnati, OH 45229, USA; (W.F.); (B.S.P.); (M.S.); (N.N.); (M.K.K.); (R.M.)
| | - Joan T. Garrett
- Department of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, Cincinnati, OH 45229, USA; (W.F.); (B.S.P.); (M.S.); (N.N.); (M.K.K.); (R.M.)
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8
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Li Y, Pan Y, Yang X, Wang Y, Liu B, Zhang Y, Gao X, Wang Y, Zhou H, Li F. Unveiling the enigmatic role of MYH9 in tumor biology: a comprehensive review. Cell Commun Signal 2024; 22:417. [PMID: 39192336 PMCID: PMC11351104 DOI: 10.1186/s12964-024-01781-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 08/06/2024] [Indexed: 08/29/2024] Open
Abstract
Non-muscle myosin heavy chain IIA (MYH9), a member of the non-muscle myosin II (NM II) family, is widely expressed in cells. The interaction of MYH9 with actin in the cytoplasm can hydrolyze ATP, completing the conversion of chemical energy to mechanical motion. MYH9 participates in various cellular processes, such as cell adhesion, migration, movement, and even signal transduction. Mutations in MYH9 are often associated with autosomal dominant platelet disorders and kidney diseases. Over the past decade, tumor-related research has gradually revealed a close relationship between MYH9 and the occurrence and development of tumors. This article provides a review of the research progress on the role of MYH9 in cancer regulation. We also discussed the anti-cancer effects of MYH9 under special circumstances, as well as its regulation of T cell function. In addition, given the importance of MYH9 as a key hub in oncogenic signal transduction, we summarize the current therapeutic strategies targeting MYH9 as well as the ongoing challenges.
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Affiliation(s)
- Yunkuo Li
- Department of Urology Il, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yujie Pan
- Department of Urology Il, The First Hospital of Jilin University, Changchun, 130021, China
| | - Xiangzhe Yang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China
| | - Yuxiong Wang
- Department of Urology Il, The First Hospital of Jilin University, Changchun, 130021, China
| | - Bin Liu
- Department of Urology Il, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yanghe Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China
| | - Xin Gao
- Department of Urology Il, The First Hospital of Jilin University, Changchun, 130021, China
| | - Yishu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, 130021, China
| | - Honglan Zhou
- Department of Urology Il, The First Hospital of Jilin University, Changchun, 130021, China
| | - Faping Li
- Department of Urology Il, The First Hospital of Jilin University, Changchun, 130021, China.
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9
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Shen K, Chen T, Xiao M. MYH9-related inherited thrombocytopenia: the genetic spectrum, underlying mechanisms, clinical phenotypes, diagnosis, and management approaches. Res Pract Thromb Haemost 2024; 8:102552. [PMID: 39309229 PMCID: PMC11415342 DOI: 10.1016/j.rpth.2024.102552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 07/16/2024] [Accepted: 07/24/2024] [Indexed: 09/25/2024] Open
Abstract
Inherited thrombocytopenias have been considered exceedingly rare for a long time, but recent advances have facilitated diagnosis and greatly enabled the discovery of new causative genes. MYH9-related disease (MYH9-RD) represents one of the most frequent forms of inherited thrombocytopenia, usually presenting with nonspecific clinical manifestations, which renders it difficult to establish an accurate diagnosis. MYH9-RD is an autosomal dominant-inherited thrombocytopenia caused by deleterious variants in the MYH9 gene encoding the heavy chain of nonmuscle myosin IIA. Patients with MYH9-RD usually present with thrombocytopenia and platelet macrocytosis at birth or in infancy, and most of them may develop one or more extrahematologic manifestations of progressive nephritis, sensorial hearing loss, presenile cataracts, and elevated liver enzymatic levels during childhood and adult life. Here, we have reviewed recent advances in the study of MYH9-RD, which aims to provide an updated and comprehensive summary of the current knowledge and improve our understanding of the genetic spectrum, underlying mechanisms, clinical phenotypes, diagnosis, and management approaches of this rare disease. Importantly, our goal is to enable physicians to better understand this rare disease and highlight the critical role of genetic etiologic analysis in ensuring accurate diagnosis, clinical management, and genetic counseling while avoiding ineffective and potentially harmful therapies for MYH9-RD patients.
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Affiliation(s)
- Kefeng Shen
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ting Chen
- Department of Ophthalmology, The Sixth Hospital of Wuhan, Affiliated Hospital of Jianghan University, Wuhan, China
| | - Min Xiao
- Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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10
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Gou Z, Zhang D, Cao H, Li Y, Li Y, Zhao Z, Wang Y, Wang Y, Zhou H. Exploring the nexus between MYH9 and tumors: novel insights and new therapeutic opportunities. Front Cell Dev Biol 2024; 12:1421763. [PMID: 39149512 PMCID: PMC11325155 DOI: 10.3389/fcell.2024.1421763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Accepted: 07/19/2024] [Indexed: 08/17/2024] Open
Abstract
The myosin heavy chain 9 (MYH9) gene, located on human chromosome 22, encodes non-muscle myosin heavy chain IIA (NM IIA). This protein is essential to various cellular events, such as generating intracellular chemomechanical force and facilitating the movement of the actin cytoskeleton. Mutations associated with thrombocytopenia in autosomal dominant diseases first highlighted the significance of the MYH9 gene. In recent years, numerous studies have demonstrated the pivotal roles of MYH9 in various cancers. However, its effects on cancer are intricate and not fully comprehended. Furthermore, the elevated expression of MYH9 in certain malignancies suggests its potential as a target for tumor therapy. Nonetheless, there is a paucity of literature summarizing MYH9's role in tumors and the therapeutic strategies centered on it, necessitating a systematic analysis. This paper comprehensively reviews and analyzes the pertinent literature in this domain, elucidating the fundamental structural characteristics, biological functions, and the nexus between MYH9 and tumors. The mechanisms through which MYH9 contributes to tumor development and its multifaceted roles in the tumorigenic process are also explored. Additionally, we discuss the relationship between MYH9-related diseases (MYH9-RD) and tumors and also summarize tumor therapeutic approaches targeting MYH9. The potential clinical applications of studying the MYH9 gene include improving early diagnosis, clinical staging, and prognosis of tumors. This paper is anticipated to provide novel insights for tumor therapy.
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Affiliation(s)
- Zixuan Gou
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Difei Zhang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Hongliang Cao
- Department of Urology II, The First Hospital of Jilin University, Changchun, China
| | - Yao Li
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Yunkuo Li
- Department of Urology II, The First Hospital of Jilin University, Changchun, China
| | - Zijian Zhao
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Ye Wang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Yishu Wang
- Key Laboratory of Pathobiology, Ministry of Education, Jilin University, Changchun, China
| | - Honglan Zhou
- Department of Urology II, The First Hospital of Jilin University, Changchun, China
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11
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Lu S, Niu Z, Qiao X. Exploring the Genotype-Phenotype Correlations in a Child with Inherited Seizure and Thrombocytopenia by Digenic Network Analysis. Genes (Basel) 2024; 15:1004. [PMID: 39202364 PMCID: PMC11353731 DOI: 10.3390/genes15081004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 07/24/2024] [Accepted: 07/27/2024] [Indexed: 09/03/2024] Open
Abstract
Understanding the correlation between genotype and phenotype remains challenging for modern genetics. Digenic network analysis may provide useful models for understanding complex phenotypes that traditional Mendelian monogenic models cannot explain. Clinical data, whole exome sequencing data, in silico, and machine learning analysis were combined to construct a digenic network that may help unveil the complex genotype-phenotype correlations in a child presenting with inherited seizures and thrombocytopenia. The proband inherited a maternal heterozygous missense variant in SCN1A (NM_001165963.4:c.2722G>A) and a paternal heterozygous missense variant in MYH9 (NM_002473.6:c.3323A>C). In silico analysis showed that these two variants may be pathogenic for inherited seizures and thrombocytopenia in the proband. Moreover, focusing on 230 epilepsy-associated genes and 35 thrombopoiesis genes, variant call format data of the proband were analyzed using machine learning tools (VarCoPP 2.0) and Digenic Effect predictor. A digenic network was constructed, and SCN1A and MYH9 were found to be core genes in the network. Further analysis showed that MYH9 might be a modifier of SCN1A, and the variant in MYH9 might not only influence the severity of SCN1A-related seizure but also lead to thrombocytopenia in the bone marrow. In addition, another eight variants might also be co-factors that account for the proband's complex phenotypes. Our data show that as a supplement to the traditional Mendelian monogenic model, digenic network analysis may provide reasonable models for the explanation of complex genotype-phenotype correlations.
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Affiliation(s)
| | | | - Xiaohong Qiao
- Department of Pediatrics, Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai 200065, China; (S.L.); (Z.N.)
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12
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Chinthalapudi K, Heissler SM. Structure, regulation, and mechanisms of nonmuscle myosin-2. Cell Mol Life Sci 2024; 81:263. [PMID: 38878079 PMCID: PMC11335295 DOI: 10.1007/s00018-024-05264-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 04/24/2024] [Accepted: 04/30/2024] [Indexed: 06/23/2024]
Abstract
Members of the myosin superfamily of molecular motors are large mechanochemical ATPases that are implicated in an ever-expanding array of cellular functions. This review focuses on mammalian nonmuscle myosin-2 (NM2) paralogs, ubiquitous members of the myosin-2 family of filament-forming motors. Through the conversion of chemical energy into mechanical work, NM2 paralogs remodel and shape cells and tissues. This process is tightly controlled in time and space by numerous synergetic regulation mechanisms to meet cellular demands. We review how recent advances in structural biology together with elegant biophysical and cell biological approaches have contributed to our understanding of the shared and unique mechanisms of NM2 paralogs as they relate to their kinetics, regulation, assembly, and cellular function.
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Affiliation(s)
- Krishna Chinthalapudi
- Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH, 43210, USA
| | - Sarah M Heissler
- Department of Physiology and Cell Biology, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University College of Medicine, Columbus, OH, 43210, USA.
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13
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Mannherz HG, Budde H, Jarkas M, Hassoun R, Malek-Chudzik N, Mazur AJ, Skuljec J, Pul R, Napirei M, Hamdani N. Reorganization of the actin cytoskeleton during the formation of neutrophil extracellular traps (NETs). Eur J Cell Biol 2024; 103:151407. [PMID: 38555846 DOI: 10.1016/j.ejcb.2024.151407] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2023] [Revised: 03/19/2024] [Accepted: 03/20/2024] [Indexed: 04/02/2024] Open
Abstract
We analyzed actin cytoskeleton alterations during NET extrusion by neutrophil-like dHL-60 cells and human neutrophils in the absence of DNase1 containing serum to avoid chromatin degradation and microfilament disassembly. NET-formation by dHL-60 cells and neutrophils was induced by Ionomycin or phorbol-12-myristat-13-acetate (PMA). Subsequent staining with anti-actin and TRITC-phalloidin showed depolymerization of the cortical F-actin at spatially confined areas, the NET extrusion sites, effected by transient activation of the monooxygenase MICAL-1 supported by the G-actin binding proteins cofilin, profilin, thymosin ß4 and probably the F-actin fragmenting activity of gelsolin and/or its fragments, which also decorated the formed NETs. MICAL-1 itself appeared to be proteolyzed by neutrophil elastase possibly to confine its activity to the NET-extrusion area. The F-actin oxidization activity of MICAL-1 is inhibited by Levosimendan leading to reduced NET-formation. Anti-gasdermin-D immunohistochemistry showed a cytoplasmic distribution in non-stimulated cells. After stimulation the NET-extrusion pore displayed reduced anti-gasdermin-D staining but accumulated underneath the plasma membrane of the remaining cell body. A similar distribution was observed for myosin that concentrated together with cortical F-actin along the periphery of the remaining cell body suggesting force production by acto-myosin interactions supporting NET expulsion as indicated by the inhibitory action of the myosin ATPase inhibitor blebbistatin. Isolated human neutrophils displayed differences in their content of certain cytoskeletal proteins. After stimulation neutrophils with high gelsolin content preferentially formed "cloud"-like NETs, whereas those with low or no gelsolin formed long "filamentous" NETs.
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Affiliation(s)
- Hans Georg Mannherz
- Department of Anatomy and Molecular Embryology, Medical Faculty, Ruhr-University Bochum, Germany; Department of Cellular and Translational Physiology, Institute of Physiology, Medical Faculty, Ruhr-University Bochum, and Molecular and Experimental Cardiology, Institute for Research and Education, St. Josef Hospital, Clinics of the Ruhr-University Bochum, Germany.
| | - Heidi Budde
- Department of Cellular and Translational Physiology, Institute of Physiology, Medical Faculty, Ruhr-University Bochum, and Molecular and Experimental Cardiology, Institute for Research and Education, St. Josef Hospital, Clinics of the Ruhr-University Bochum, Germany.
| | - Muhammad Jarkas
- Department of Cellular and Translational Physiology, Institute of Physiology, Medical Faculty, Ruhr-University Bochum, and Molecular and Experimental Cardiology, Institute for Research and Education, St. Josef Hospital, Clinics of the Ruhr-University Bochum, Germany.
| | - Roua Hassoun
- Department of Cellular and Translational Physiology, Institute of Physiology, Medical Faculty, Ruhr-University Bochum, and Molecular and Experimental Cardiology, Institute for Research and Education, St. Josef Hospital, Clinics of the Ruhr-University Bochum, Germany.
| | - Natalia Malek-Chudzik
- Department of Chemical Biology and Bioimaging, Faculty of Chemistry, University of Wroclaw, Poland.
| | - Antonina J Mazur
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Poland.
| | - Jelena Skuljec
- Department of Neurology, University Medicine Essen, Germany; Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, Germany.
| | - Refik Pul
- Department of Neurology, University Medicine Essen, Germany; Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Medicine Essen, Germany.
| | - Markus Napirei
- Department of Anatomy and Molecular Embryology, Medical Faculty, Ruhr-University Bochum, Germany
| | - Nazha Hamdani
- Department of Cellular and Translational Physiology, Institute of Physiology, Medical Faculty, Ruhr-University Bochum, and Molecular and Experimental Cardiology, Institute for Research and Education, St. Josef Hospital, Clinics of the Ruhr-University Bochum, Germany; Department of Physiology, University Maastricht, Maastricht, the Netherlands; HCEMM-SU Cardiovascular Comorbidities Research Group, Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest 1089, Hungary.
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14
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Niwa K, Toyoda H, Kohso A, Okumura Y, Kunishima S, Hirayama M. Case Report: MYH9-related disease caused by Ala44Pro mutation in a child with a previous diagnosis of chronic immune thrombocytopenia. Front Pediatr 2024; 12:1391742. [PMID: 38827217 PMCID: PMC11140069 DOI: 10.3389/fped.2024.1391742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 04/25/2024] [Indexed: 06/04/2024] Open
Abstract
MYH9-related disease, a rare autosomal dominant platelet disorder characterized by thrombocytopenia, giant platelets, and leukocyte inclusion bodies, may mimic immune thrombocytopenia in children unless suspected and carefully excluded. Here, we present a case involving a three-year-old girl with mild bleeding symptoms since infancy, previously diagnosed with chronic immune thrombocytopenia. The patient exhibited isolated thrombocytopenia and lacked any family history of thrombocytopenia, hearing impairment, or renal failure. Examination of peripheral blood smears via light microscopy revealed significant platelet macrocytosis with giant platelets and basophilic Döhle-like bodies in the neutrophils. Subsequent sequencing analysis of MYH9 gene identified a p.Ala44Pro mutation. Throughout a six-year follow-up period, the patient's condition remained stable. Our report underscores the significance of identifying leukocyte inclusion bodies in peripheral blood smears and considering MYH9-related diseases, even in instances of chronic macrothrombocytopenia devoid of familial history or non-hematological manifestations.
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Affiliation(s)
- Kaori Niwa
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan
| | - Hidemi Toyoda
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan
| | - Atsushi Kohso
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan
| | - Yosuke Okumura
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan
| | - Shinji Kunishima
- Department of Medical Technology, Gifu University of Medical Science, Gifu, Japan
| | - Masahiro Hirayama
- Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Japan
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15
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De Coninck S, De Smedt R, Lintermans B, Reunes L, Kosasih HJ, Reekmans A, Brown LM, Van Roy N, Palhais B, Roels J, Van der Linden M, Van Dorpe J, Ntziachristos P, Van Delft FW, Mansour MR, Pieters T, Lammens T, De Moerloose B, De Bock CE, Goossens S, Van Vlierberghe P. Targeting hyperactive platelet-derived growth factor receptor-β signaling in T-cell acute lymphoblastic leukemia and lymphoma. Haematologica 2024; 109:1373-1384. [PMID: 37941480 PMCID: PMC11063843 DOI: 10.3324/haematol.2023.283981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 11/02/2023] [Indexed: 11/10/2023] Open
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are rare aggressive hematologic malignancies. Current treatment consists of intensive chemotherapy leading to 80% overall survival but is associated with severe toxic side effects. Furthermore, 10-20% of patients still die from relapsed or refractory disease providing a strong rationale for more specific, targeted therapeutic strategies with less toxicities. Here, we report a novel MYH9::PDGFRB fusion in a T-LBL patient, and demonstrate that this fusion product is constitutively active and sufficient to drive oncogenic transformation in vitro and in vivo. Expanding our analysis more broadly across T-ALL, we found a T-ALL cell line and multiple patient-derived xenograft models with PDGFRB hyperactivation in the absence of a fusion, with high PDGFRB expression in TLX3 and HOXA T-ALL molecular subtypes. To target this PDGFRB hyperactivation, we evaluated the therapeutic effects of a selective PDGFRB inhibitor, CP-673451, both in vitro and in vivo and demonstrated sensitivity if the receptor is hyperactivated. Altogether, our work reveals that hyperactivation of PDGFRB is an oncogenic driver in T-ALL/T-LBL, and that screening T-ALL/T-LBL patients for phosphorylated PDGFRB levels can serve as a biomarker for PDGFRB inhibition as a novel targeted therapeutic strategy in their treatment regimen.
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Affiliation(s)
- Stien De Coninck
- Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent
| | - Renate De Smedt
- Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent
| | - Beatrice Lintermans
- Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent
| | - Lindy Reunes
- Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, 9000 Ghent
| | - Hansen J Kosasih
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia; School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Sydney, NSW
| | - Alexandra Reekmans
- Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent
| | - Lauren M Brown
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia; School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Sydney, NSW
| | - Nadine Van Roy
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Lab for Translational Oncogenomics and Bioinformatics, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Pediatric Precision Oncology Lab, Department of Biomolecular Medicine, Ghent University, 9000 Ghent
| | - Bruno Palhais
- Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, 9000 Ghent
| | - Juliette Roels
- Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent
| | - Malaika Van der Linden
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Pathology, Ghent University and Ghent University Hospital, 9000 Ghent
| | - Jo Van Dorpe
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Pathology, Ghent University and Ghent University Hospital, 9000 Ghent
| | - Panagiotis Ntziachristos
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, 9000 Ghent
| | - Frederik W Van Delft
- Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle upon Tyne
| | - Marc R Mansour
- Department of Developmental Biology and Cancer, Institute of Child Health, University College London
| | - Tim Pieters
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Biomolecular Medicine, Ghent University, 9000 Ghent
| | - Tim Lammens
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Internal Medicine and Pediatrics, Ghent University, 9000 Ghent, Belgium; Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent
| | - Barbara De Moerloose
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, 9000 Ghent
| | - Charles E De Bock
- Children's Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia; School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Sydney, NSW
| | - Steven Goossens
- Cancer Research Institute Ghent (CRIG), 9000 Ghent, Belgium; Unit for Translational Research in Oncology, Department of Diagnostic Sciences, Ghent University, 9000 Ghent.
| | - Pieter Van Vlierberghe
- Lab of Normal and Malignant Hematopoiesis, Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), 9000 Ghent
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16
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Garrido-Casado M, Asensio-Juárez G, Talayero VC, Vicente-Manzanares M. Engines of change: Nonmuscle myosin II in mechanobiology. Curr Opin Cell Biol 2024; 87:102344. [PMID: 38442667 DOI: 10.1016/j.ceb.2024.102344] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 02/04/2024] [Accepted: 02/05/2024] [Indexed: 03/07/2024]
Abstract
The emergence of mechanobiology has unveiled complex mechanisms by which cells adjust intracellular force production to their needs. Most communicable intracellular forces are generated by myosin II, an actin-associated molecular motor that transforms adenosine triphosphate (ATP) hydrolysis into contraction in nonmuscle and muscle cells. Myosin II-dependent force generation is tightly regulated, and deregulation is associated with specific pathologies. Here, we focus on the role of myosin II (nonmuscle myosin II, NMII) in force generation and mechanobiology. We outline the regulation and molecular mechanism of force generation by NMII, focusing on the actual outcome of contraction, that is, force application to trigger mechanosensitive events or the building of dissipative structures. We describe how myosin II-generated forces drive two major types of events: modification of the cellular morphology and/or triggering of genetic programs, which enhance the ability of cells to adapt to, or modify, their microenvironment. Finally, we address whether targeting myosin II to impair or potentiate its activity at the motor level is a viable therapeutic strategy, as illustrated by recent examples aimed at modulating cardiac myosin II function in heart disease.
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Affiliation(s)
- Marina Garrido-Casado
- Molecular Mechanisms Program, Centro de Investigación del Cáncer/ Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, 37007 Salamanca, Spain
| | - Gloria Asensio-Juárez
- Molecular Mechanisms Program, Centro de Investigación del Cáncer/ Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, 37007 Salamanca, Spain
| | - Vanessa C Talayero
- Molecular Mechanisms Program, Centro de Investigación del Cáncer/ Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, 37007 Salamanca, Spain
| | - Miguel Vicente-Manzanares
- Molecular Mechanisms Program, Centro de Investigación del Cáncer/ Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC) and University of Salamanca, 37007 Salamanca, Spain.
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17
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Fostier W, Husain A, Rajan N. Squamous cell carcinoma and MYH9-associated elastin aggregation (MALTA) syndrome. Clin Exp Dermatol 2023; 49:105-107. [PMID: 37708298 DOI: 10.1093/ced/llad263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2022] [Revised: 05/08/2023] [Accepted: 08/04/2023] [Indexed: 09/16/2023]
Abstract
MYH9-associated elastin aggregation (MALTA) syndrome is a rare inherited syndrome of irregular elastin aggregation and sweat duct proliferation associated with pathogenic variants in MYH9. MALTA syndrome was first proposed in 2019, unifying Nicolau–Balus and Rombo syndromes as phenotypes arising from pathogenic variants in the same gene; however, it has not been associated with cutaneous squamous cell carcinoma (cSCC). Here, we report the clinical features of a family with a novel MYH9 c.1952A>C p.(Lys651Thr) pathogenic variant, providing evidence that cSCC development may be an associated feature of MALTA syndrome.
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Affiliation(s)
- William Fostier
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
| | | | - Neil Rajan
- Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK
- Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, UK
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18
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Cao Q, Zhu H, Xu W, Zhang R, Wang Y, Tian Z, Yuan Y. Predicting the efficacy of glucocorticoids in pediatric primary immune thrombocytopenia using plasma proteomics. Front Immunol 2023; 14:1301227. [PMID: 38162645 PMCID: PMC10757608 DOI: 10.3389/fimmu.2023.1301227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Accepted: 12/04/2023] [Indexed: 01/03/2024] Open
Abstract
Objective Primary immune thrombocytopenia (ITP) is the most common acquired autoimmune bleeding disorder among children. While glucocorticoids are the primary first-line treatment for ITP treatment, they prove ineffective in certain patients. The challenge of identifying biomarkers capable of early prediction regarding the response to glucocorticoid therapy in ITP persists. This study aimed to identify ideal biomarkers for predicting glucocorticoid efficacy in patients with ITP using plasma proteomics. Methods A four-dimensional data-independent acquisition approach was performed to determine the differentially expressed proteins in plasma samples collected from glucocorticoid-sensitive (GCS) (n=18) and glucocorticoid-resistant (GCR) (n=17) children with ITP treated with prednisone. The significantly differentially expressed proteins were selected for enzyme-linked immunosorbent assay validation in a cohort conprising 65 samples(30 healthy controls, 18 GCS and 17 GCR children with ITP). Receiver operating characteristics curves, calibration curves, and clinical decision curve analysis were used to determine the diagnostic efficacy of this method. Results 47 differentially expressed proteins (36 up-regulated and 11 down-regulated) were identified in the GCR group compared with the GCS group. The significantly differentially expressed proteins myosin heavy chain 9 (MYH9) and fetuin B (FETUB) were selected for enzyme-linked immunosorbent assay validation. The validation results were consistent with the proteomics analyses. Compared with the GCS group, the GCR group exhibited a significantly reduced the plasma concentration of MYH9 and elevated the plasma concentration of FETUB. Furthermore, the receiver operating characteristics curves, calibration curves, and clinical decision curve analysis demonstrated good diagnostic efficacy of these validated biomarkers. Conclusion This study contributes to the establishment of objective biological indicators for precision therapy in children with ITP. More importantly, the proteins MYH9 and FETUB hold potential as a foundation for making informed decisions regarding alternative treatments for drugresistant patients, thereby preventing treatment delays.
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Affiliation(s)
- Qingqing Cao
- Department of Pediatrics, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, China
| | - Haiyan Zhu
- Department of Pediatrics, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, China
| | - Wei Xu
- Department of Pediatrics, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, China
| | - Rongrong Zhang
- Department of Pediatrics, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, China
| | - Yun Wang
- Department of Pediatrics, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, China
| | - Zhaofang Tian
- Department of Neonatology, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, China
| | - Yufang Yuan
- Department of Pediatrics, The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University, Huai’an, China
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19
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Chen D, Pruthi RK. Platelet genetic testing by next-generation sequencing: A practical update. Int J Lab Hematol 2023; 45:630-642. [PMID: 37463678 DOI: 10.1111/ijlh.14136] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Accepted: 06/27/2023] [Indexed: 07/20/2023]
Abstract
Inherited platelet disorders (IPDs) are a heterogeneous group of disorders characterized by normal or reduced platelet counts, bleeding diatheses of varying severities, and the presence (syndromic) or absence (non-syndromic) of involvement of other organs. Due to the lack of highly specific platelet function tests and overlapping clinical and laboratory features, diagnosing the underlying cause of IPDs remains challenging. In recent years, genetic testing via next-generation sequencing (NGS) technologies to rapidly analyze multiple genes has gradually emerged as an important part of the laboratory investigation of patients with IPDs. A systemic clinical and laboratory testing approach and thorough phenotype and genotype correlation studies of both patients and their family members are crucial for accurate diagnoses of IPDs.
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Affiliation(s)
- Dong Chen
- Special Coagulation Laboratory, Division of Hematopathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Rajiv K Pruthi
- Special Coagulation Laboratory, Division of Hematopathology, Mayo Clinic, Rochester, Minnesota, USA
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Mercaldo V, Vidimova B, Gastaldo D, Fernández E, Lo AC, Cencelli G, Pedini G, De Rubeis S, Longo F, Klann E, Smit AB, Grant SGN, Achsel T, Bagni C. Altered striatal actin dynamics drives behavioral inflexibility in a mouse model of fragile X syndrome. Neuron 2023; 111:1760-1775.e8. [PMID: 36996810 DOI: 10.1016/j.neuron.2023.03.008] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 12/21/2022] [Accepted: 03/06/2023] [Indexed: 03/31/2023]
Abstract
The proteome of glutamatergic synapses is diverse across the mammalian brain and involved in neurodevelopmental disorders (NDDs). Among those is fragile X syndrome (FXS), an NDD caused by the absence of the functional RNA-binding protein FMRP. Here, we demonstrate how the brain region-specific composition of postsynaptic density (PSD) contributes to FXS. In the striatum, the FXS mouse model shows an altered association of the PSD with the actin cytoskeleton, reflecting immature dendritic spine morphology and reduced synaptic actin dynamics. Enhancing actin turnover with constitutively active RAC1 ameliorates these deficits. At the behavioral level, the FXS model displays striatal-driven inflexibility, a typical feature of FXS individuals, which is rescued by exogenous RAC1. Striatal ablation of Fmr1 is sufficient to recapitulate behavioral impairments observed in the FXS model. These results indicate that dysregulation of synaptic actin dynamics in the striatum, a region largely unexplored in FXS, contributes to the manifestation of FXS behavioral phenotypes.
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Affiliation(s)
- Valentina Mercaldo
- Department of Fundamental Neurosciences, Université de Lausanne, 1005 Lausanne, Switzerland
| | - Barbora Vidimova
- Department of Fundamental Neurosciences, Université de Lausanne, 1005 Lausanne, Switzerland
| | - Denise Gastaldo
- Department of Fundamental Neurosciences, Université de Lausanne, 1005 Lausanne, Switzerland
| | - Esperanza Fernández
- VIB & UGent Center for Medical Biotechnology, Universiteit Gent, 9052 Ghent, Belgium
| | - Adrian C Lo
- Department of Fundamental Neurosciences, Université de Lausanne, 1005 Lausanne, Switzerland
| | - Giulia Cencelli
- Department of Biomedicine and Prevention, Università degli Studi di Roma "Tor Vergata", 00133 Rome, Italy; Institute of Neurosurgery, Fondazione Policlinico Universitario A. Gemelli IRCCS - Università Cattolica del Sacro Cuore, 00168 Rome, Italy
| | - Giorgia Pedini
- Department of Biomedicine and Prevention, Università degli Studi di Roma "Tor Vergata", 00133 Rome, Italy
| | - Silvia De Rubeis
- Seaver Autism Center for Research and Treatment, Department of Psychiatry, Friedman Brain Institute, Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Francesco Longo
- Center for Neural Science, New York University, New York, NY 10029, USA
| | - Eric Klann
- Center for Neural Science, New York University, New York, NY 10029, USA
| | - August B Smit
- Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands
| | - Seth G N Grant
- Center for the Clinical Brain Sciences and Simons Initiatives for the Developing Brain, The University of Edinburgh, Edinburgh EH16 4SB, Scotland
| | - Tilmann Achsel
- Department of Fundamental Neurosciences, Université de Lausanne, 1005 Lausanne, Switzerland.
| | - Claudia Bagni
- Department of Fundamental Neurosciences, Université de Lausanne, 1005 Lausanne, Switzerland; Department of Biomedicine and Prevention, Università degli Studi di Roma "Tor Vergata", 00133 Rome, Italy.
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21
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Alanazi SM, Feroz W, Mishra R, Kilroy MK, Patel H, Yuan L, Storr SJ, Garrett JT. HER2 inhibition increases non-muscle myosin IIA to promote tumorigenesis in HER2+ breast cancers. PLoS One 2023; 18:e0285251. [PMID: 37200287 PMCID: PMC10194889 DOI: 10.1371/journal.pone.0285251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 04/18/2023] [Indexed: 05/20/2023] Open
Abstract
HER2 is over-expressed in around 15% to 20% of breast cancers. HER3 plays a critical role in HER2 mediated tumorigenesis. Increased HER3 transcription and protein levels occur upon inhibition of HER2. We aimed to identify proteins that bound to HER3 upon inhibition of the HER family with the pan-HER inhibitor neratinib in HER2+ breast cancer cells. Immunoprecipitation of HER3 followed by mass spectrometry experiments found non-muscle myosin IIA (NMIIA) increased upon neratinib treatment relative to vehicle DMSO treatment. MYH9 is the gene that encodes for the heavy chain of NMIIA. Breast cancer patients with high MYH9 were significantly associated with a shorter disease specific survival compared to patients with low MYH9 expression from the METABRIC cohort of patients. In addition, high MYH9 expression was associated with HER2+ tumors from this cohort. Immunoblots of whole cell lysates of BT474 and MDA-MB-453 HER2+ breast cancer cells demonstrated elevated HER3 and NMIIA protein levels upon neratinib treatment for 24 hours. To examine the role of NMIIA in HER2+ breast cancer, we modulated NMIIA levels in BT474 and MDA-MB-453 cells using doxycycline inducible shRNA targeting MYH9. MYH9 knockdown reduces HER3 protein levels and concomitant reduction in downstream P-Akt. In addition, loss of MYH9 suppresses cell growth, proliferation, migration, and invasion. Our data reveals that NMIIA regulates HER3 and loss of NMIIA reduces HER2+ breast cancer growth.
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Affiliation(s)
- Samar M. Alanazi
- James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States of America
| | - Wasim Feroz
- James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States of America
| | - Rosalin Mishra
- James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States of America
| | - Mary Kate Kilroy
- James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States of America
| | - Hima Patel
- James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States of America
| | - Long Yuan
- James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States of America
| | - Sarah J. Storr
- Nottingham Breast Cancer Research Centre, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, United Kingdom
| | - Joan T. Garrett
- James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, United States of America
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22
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Mahé C, Lavigne R, Com E, Pineau C, Zlotkowska AM, Tsikis G, Mermillod P, Schoen J, Saint-Dizier M. The sperm-interacting proteome in the bovine isthmus and ampulla during the periovulatory period. J Anim Sci Biotechnol 2023; 14:30. [PMID: 36797800 PMCID: PMC9936689 DOI: 10.1186/s40104-022-00811-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Accepted: 11/24/2022] [Indexed: 02/18/2023] Open
Abstract
BACKGROUND Spermatozoa interact with oviduct secretions before fertilization in vivo but the molecular players of this dialog and underlying dynamics remain largely unknown. Our objectives were to identify an exhaustive list of sperm-interacting proteins (SIPs) in the bovine oviduct fluid and to evaluate the impact of the oviduct anatomical region (isthmus vs. ampulla) and time relative to ovulation (pre-ovulatory vs. post-ovulatory) on SIPs number and abundance. METHODS Pools of oviduct fluid (OF) from the pre-ovulatory ampulla, pre-ovulatory isthmus, post-ovulatory ampulla, and post-ovulatory isthmus in the side of ovulation were collected from the slaughterhouse. Frozen-thawed bull sperm were incubated with OF or phosphate-buffered saline (control) for 60 min at 38.5 °C. After protein extraction and digestion, sperm and OF samples were analyzed by nanoLC-MS/MS and label-free protein quantification. RESULTS A quantitative comparison between proteins identified in sperm and OF samples (2333 and 2471 proteins, respectively) allowed for the identification of 245 SIPs. The highest number (187) were found in the pre-ovulatory isthmus, i.e., time and place of the sperm reservoir. In total, 41 SIPs (17%) were differentially abundant between stages in a given region or between regions at a given stage and 76 SIPs (31%) were identified in only one region × stage condition. Functional analysis of SIPs predicted roles in cell response to stress, regulation of cell motility, fertilization, and early embryo development. CONCLUSION This study provides a comprehensive list of SIPs in the bovine oviduct and evidences dynamic spatio-temporal changes in sperm-oviduct interactions around ovulation time. Moreover, these data provide protein candidates to improve sperm conservation and in vitro fertilization media.
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Affiliation(s)
- Coline Mahé
- CNRS, IFCE, INRAE, Université de Tours, PRC, 37380, Nouzilly, France.
| | - Régis Lavigne
- grid.410368.80000 0001 2191 9284Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement Et Travail) - UMR-S 1085, F-35000 Rennes, France ,grid.410368.80000 0001 2191 9284Univ Rennes, CNRS, Inserm, Biosit UAR 3480 US_S 018, Protim Core Facility, 35000 Rennes, France
| | - Emmanuelle Com
- grid.410368.80000 0001 2191 9284Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement Et Travail) - UMR-S 1085, F-35000 Rennes, France ,grid.410368.80000 0001 2191 9284Univ Rennes, CNRS, Inserm, Biosit UAR 3480 US_S 018, Protim Core Facility, 35000 Rennes, France
| | - Charles Pineau
- grid.410368.80000 0001 2191 9284Univ Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement Et Travail) - UMR-S 1085, F-35000 Rennes, France ,grid.410368.80000 0001 2191 9284Univ Rennes, CNRS, Inserm, Biosit UAR 3480 US_S 018, Protim Core Facility, 35000 Rennes, France
| | - Aleksandra Maria Zlotkowska
- grid.418188.c0000 0000 9049 5051Institute of Reproductive Biology, Leibniz Institute for Farm Animal Biology, FBN, Dummerstorf, Germany ,grid.418779.40000 0001 0708 0355Present Address: Department of Reproduction Biology, Leibniz Institute for Zoo and Wildlife Research (IZW), Berlin, Germany
| | - Guillaume Tsikis
- grid.464126.30000 0004 0385 4036CNRS, IFCE, INRAE, Université de Tours, PRC, 37380 Nouzilly, France
| | - Pascal Mermillod
- grid.464126.30000 0004 0385 4036CNRS, IFCE, INRAE, Université de Tours, PRC, 37380 Nouzilly, France
| | - Jennifer Schoen
- grid.418188.c0000 0000 9049 5051Institute of Reproductive Biology, Leibniz Institute for Farm Animal Biology, FBN, Dummerstorf, Germany ,grid.418779.40000 0001 0708 0355Present Address: Department of Reproduction Biology, Leibniz Institute for Zoo and Wildlife Research (IZW), Berlin, Germany
| | - Marie Saint-Dizier
- grid.464126.30000 0004 0385 4036CNRS, IFCE, INRAE, Université de Tours, PRC, 37380 Nouzilly, France
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23
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Jiang B, Hartzell M, Yu S, Masab M, Lyckholm L. Venous thromboembolism prophylaxis of a patient with MYH-9 related disease and COVID-19 infection: A case report. World J Hematol 2023; 10:1-8. [DOI: 10.5315/wjh.v10.i1.1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 10/06/2022] [Accepted: 12/06/2022] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND The May-Hegglin anomaly is among a group of genetic disorders known as MYH9-related disease. Patients with inherited platelet disorders such as May-Hegglin anomaly are at a variably increased risk for bleeding due to a com-bination of platelet dysfunction and thrombocytopenia. Patients admitted to the hospital with coronavirus disease 2019 (COVID-19) infection are at an increased risk for a venous thromboembolism event (VTE). The National Institutes of Health COVID-19 treatment guidelines recommend using a prophylactic dose of heparin as VTE prophylaxis for adults who are receiving high-flow oxygen. We describe a patient admitted for COVID-19 infection with pneumonia and a history of May-Hegglin anomaly. The patient presented a challenge to determine prophylactic anticoagulation as there are no clear guidelines for this patient population.
CASE SUMMARY Herein, we describe the case of a 39-year-old woman admitted with acute hypoxic respiratory failure secondary to COVID-19 pneumonia. She had a history of May-Hegglin anomaly and demonstrated risk for bleeding since childhood, including a life-threatening bleeding event at the age of 9 years requiring blood and platelet transfusions. Her baseline platelet count was 40-50 × 109/L throughout her adult life. Her family history was also notable for May-Hegglin disorder in her mother, maternal uncle, maternal grandfather and her son. Computed tomography/ pulmonary angiography revealed bilateral consolidative opacities consistent with multifocal pneumonia. Complete blood count was notable for platelet count of 54 × 109/L. She was admitted for inpatient respiratory support with high-flow oxygen per nasal cannula and was managed with guideline-directed therapy for COVID-19, including baricitinib and dexamethasone. The Hematology/Oncology consultation team was requested to assist with management of VTE prophylaxis in the setting of active COVID-19 infection and an inherited bleeding disorder. After review of the literature and careful consideration of risks and benefits, it was decided to treat the patient with prophylactic enoxaparin. She was closely monitored in the hospital for bleeding and worsening thrombocytopenia. She had no bleeding or signs of VTE. Her respiratory status improved, and she was discharged home after 5 d of hospitalization with supplemental oxygen by nasal cannula and dexamethasone. At the 6-month follow-up, the patient successfully discontinued her home oxygen use after only a few weeks following discharge.
CONCLUSION The patient presented a challenge to determine prophylactic anticoagulation as anticoagulation guidelines exist for patients with COVID-19, but there are no clear guidelines for management of patients with COVID-19 and inherited bleeding disorders, particularly those with MYH9- related disease. She was discharged after recovery from the COVID-19 infection without bleeding or thrombosis. As there are no published guidelines for this situation, we present a pragmatic, informed approach to a patient with MYH9-related disease who had an indication for anticoagulation.
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Affiliation(s)
- Bei Jiang
- Department of Hematology and Oncology, West Virginia University, Morgantown, WV 26505, United States
| | - Michelle Hartzell
- Department of Internal Medicine, West Virginia University, Morgantown, WV 26505, United States
| | - Stephen Yu
- Department of Internal Medicine, West Virginia University, Morgantown, WV 26505, United States
| | - Muhammad Masab
- Department of Hematology and Oncology, West Virginia University, Morgantown, WV 26505, United States
| | - Laurel Lyckholm
- Department of Hematology and Oncology, West Virginia University, Morgantown, WV 26505, United States
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Wang X, Wang Z, Liu B, Jin R, Song Y, Fei R, Cong X, Huang R, Li X, Yang J, Wei L, Rao H, Liu F. Characteristic gene expression in the liver monocyte-macrophage-DC system is associated with the progression of fibrosis in NASH. Front Immunol 2023; 14:1098056. [PMID: 36911682 PMCID: PMC9998489 DOI: 10.3389/fimmu.2023.1098056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2022] [Accepted: 02/06/2023] [Indexed: 02/26/2023] Open
Abstract
Background The monocyte-macrophage-dendritic cell (DC) (MMD) system exerts crucial functions that may modulate fibrogenesis in nonalcoholic steatohepatitis (NASH). In this study, we explored the cell characteristics, distribution and developmental trajectory of the liver MMD system in NASH mice with fibrosis and clarified characteristic genes of the MMD system involved in liver fibrosis progression in NASH mice and patients. Methods Single cells in liver tissue samples from NASH and normal mice were quantified using single-cell RNA sequencing (scRNA-seq) analysis. Differentially expressed genes (DEGs) in the MMD system by pseudotime analysis were validated by tyramide signal amplification (TSA)-immunohistochemical staining (IHC) and analyzed by second harmonic generation (SHG)/two-photon excitation fluorescence (TPEF). Results Compared with control mice, there were increased numbers of monocytes, Kupffer cells, and DCs in two NASH mouse models. From the transcriptional profiles of these single cells, we identified 8 monocyte subsets (Mono1-Mono8) with different molecular and functional properties. Furthermore, the pseudotime analysis showed that Mono5 and Mono6 were at the beginning of the trajectory path, whereas Mono2, Mono4, Kupffer cells and DCs were at a terminal state. Genes related to liver collagen production were at the late stage of this trajectory path. DEGs analysis revealed that the genes Fmnl1 and Myh9 in the MMD system were gradually upregulated during the trajectory. By TSA-IHC, the Fmnl1 and Myh9 expression levels were increased and associated with collagen production and fibrosis stage in NASH mice and patients. Conclusions Our transcriptome data provide a novel landscape of the MMD system that is involved in advanced NASH disease status. Fmnl1 and Myh9 expression in the MMD system was associated with the progression of NASH fibrosis.
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Affiliation(s)
- Xiaoxiao Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Zilong Wang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Baiyi Liu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Rui Jin
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Yuyun Song
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Ran Fei
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Xu Cong
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Rui Huang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Xiaohe Li
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Jia Yang
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Lai Wei
- Beijing Tsinghua Changgung Hospital, Tsinghua University, Beijing, China
| | - Huiying Rao
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
| | - Feng Liu
- Peking University People's Hospital, Peking University Hepatology Institute, Beijing Key Laboratory of Hepatitis C and Immunotherapy for Liver Diseases, Beijing International Cooperation Base for Science and Technology on NAFLD Diagnosis, Beijing, China
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25
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Olson MF. Actin-Myosin Cytoskeleton Regulation and Function. Cells 2022; 12:cells12010009. [PMID: 36611802 PMCID: PMC9818783 DOI: 10.3390/cells12010009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
The shape and load bearing strength of cells are determined by the complex protein network comprising the actin-myosin cytoskeleton [...].
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Affiliation(s)
- Michael F Olson
- Department of Chemistry and Biology, Toronto Metropolitan University, Toronto, ON M5G 2K3, Canada
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26
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Regulation of lens water content: Effects on the physiological optics of the lens. Prog Retin Eye Res 2022:101152. [DOI: 10.1016/j.preteyeres.2022.101152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/21/2022] [Accepted: 11/22/2022] [Indexed: 12/09/2022]
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A familial case of MYH9 gene mutation associated with multiple functional and structural platelet abnormalities. Sci Rep 2022; 12:19975. [PMID: 36404341 PMCID: PMC9676191 DOI: 10.1038/s41598-022-24098-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 11/09/2022] [Indexed: 11/21/2022] Open
Abstract
Mutations in the MYH9 gene result in macrothrombocytopenia often associated with hemorrhages. Here, we studied the function and structure of platelets in three family members with a heterozygous mutation R1933X in the MYH9 gene, characteristic of closely related disorders known as the May-Hegglin anomaly and Sebastian syndrome. The examination included complete blood count, blood smear microscopy, platelet flow cytometry (expression of P-selectin and active integrin αIIbβ3 before and after activation), the kinetics of platelet-driven contraction (retraction) of blood clots, as well as scanning/transmission electron microscopy of platelets. Despite severe thrombocytopenia ranging (36-86) × 109/l, none of the patients had hemorrhages at the time of examination, although they had a history of heavy menstruation, spontaneous ecchymosis, and postpartum hemorrhage. Flow cytometry showed background platelet activation, revealed by overexpression of P-selectin and active αIIbβ3 integrin above normal levels. After TRAP-induced stimulation, the fractions of platelets expressing P-selectin in the proband and her sister were below normal response, indicating partial platelet refractoriness. The initiation of clot contraction was delayed. Electron microscopy revealed giant platelets with multiple filopodia and fusion of α-granules with dilated open canalicular system, containing filamentous and vesicular inclusions. The novel concept implies that the R1933X mutation in the MYH9 gene is associated not only with thrombocytopenia, but also with qualitative structural and functional defects in platelets. Platelet dysfunction includes impaired contractility, which can disrupt the compaction of hemostatic clots, making the clots weak and permeable, therefore predisposing patients with MYH9 gene mutations to the hemorrhagic phenotype.
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28
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Ren X, Zhu H, Deng K, Ning X, Li L, Liu D, Yang B, Shen C, Wang X, Wu N, Chen S, Gu D, Wang L. Long Noncoding RNA TPRG1-AS1 Suppresses Migration of Vascular Smooth Muscle Cells and Attenuates Atherogenesis via Interacting With MYH9 Protein. Arterioscler Thromb Vasc Biol 2022; 42:1378-1397. [PMID: 36172865 DOI: 10.1161/atvbaha.122.318158] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Migration of human aortic smooth muscle cells (HASMCs) contributes to the pathogenesis of atherosclerosis. This study aims to functionally characterize long noncoding RNA TPRG1-AS1 (tumor protein p63 regulated 1, antisense 1) in HASMCs and reveal the underlying mechanism of TPRG1-AS1 in HASMCs migration, neointima formation, and subsequent atherosclerosis. METHODS The expression of TPRG1-AS1 in atherosclerotic plaques was verified a series of in silico analysis and quantitative real-time polymerase chain reaction analysis. Northern blot, rapid amplification of cDNA ends and Sanger sequencing were used to determine its full length. In vitro transcription-translation assay was used to investigate the protein-coding capacity of TPRG1-AS1. RNA fluorescent in situ hybridization was used to confirm its subcellular localization. Loss- and gain-of-function studies were used to investigate the function of TPRG1-AS1. Furthermore, the effect of TPRG1-AS1 on the pathological response was evaluated in carotid balloon injury model, wire injury model, and atherosclerosis model, respectively. RESULTS TPRG1-AS1 was significantly increased in atherosclerotic plaques. TPRG1-AS1 did not encode any proteins and its full length was 1279nt, which was bona fide a long noncoding RNA. TPRG1-AS1 was mainly localized in cytoplasmic and perinuclear regions in HASMCs. TPRG1-AS1 directly interacted with MYH9 (myosin heavy chain 9) protein in HASMCs, promoted MYH9 protein degradation through the proteasome pathway, hindered F-actin stress fiber formation, and finally inhibited HASMCs migration. Vascular smooth muscle cell-specific transgenic overexpression of TPRG1-AS1 significantly reduced neointima formation, and attenuated atherosclerosis in apolipoprotein E knockout (Apoe-/-) mice. CONCLUSIONS This study demonstrated that TPRG1-AS1 inhibited HASMCs migration through interacting with MYH9 protein and consequently suppressed neointima formation and atherosclerosis.
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Affiliation(s)
- Xiaoxiao Ren
- Key Laboratory of Cardiovascular Epidemiology and Department of Epidemiology, State Key Laboratory of Cardiovascular Disease (X.R., H.Z., K.D., X.N., D.L., B.Y., S.C., D.G., L.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Huijuan Zhu
- Key Laboratory of Cardiovascular Epidemiology and Department of Epidemiology, State Key Laboratory of Cardiovascular Disease (X.R., H.Z., K.D., X.N., D.L., B.Y., S.C., D.G., L.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Keyong Deng
- Key Laboratory of Cardiovascular Epidemiology and Department of Epidemiology, State Key Laboratory of Cardiovascular Disease (X.R., H.Z., K.D., X.N., D.L., B.Y., S.C., D.G., L.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiaotong Ning
- Key Laboratory of Cardiovascular Epidemiology and Department of Epidemiology, State Key Laboratory of Cardiovascular Disease (X.R., H.Z., K.D., X.N., D.L., B.Y., S.C., D.G., L.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lin Li
- Key Laboratory of Cardiovascular Epidemiology and Department of Epidemiology, State Key Laboratory of Cardiovascular Disease (X.R., H.Z., K.D., X.N., D.L., B.Y., S.C., D.G., L.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dan Liu
- Key Laboratory of Cardiovascular Epidemiology and Department of Epidemiology, State Key Laboratory of Cardiovascular Disease (X.R., H.Z., K.D., X.N., D.L., B.Y., S.C., D.G., L.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Bin Yang
- Key Laboratory of Cardiovascular Epidemiology and Department of Epidemiology, State Key Laboratory of Cardiovascular Disease (X.R., H.Z., K.D., X.N., D.L., B.Y., S.C., D.G., L.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Chenyang Shen
- Department of Vascular Surgery, State Key Laboratory of Cardiovascular Disease (C.S.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xianqiang Wang
- Department of Surgery (X.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Naqiong Wu
- Cardiometabolic Center (N.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Shufeng Chen
- Key Laboratory of Cardiovascular Epidemiology and Department of Epidemiology, State Key Laboratory of Cardiovascular Disease (X.R., H.Z., K.D., X.N., D.L., B.Y., S.C., D.G., L.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Dongfeng Gu
- Key Laboratory of Cardiovascular Epidemiology and Department of Epidemiology, State Key Laboratory of Cardiovascular Disease (X.R., H.Z., K.D., X.N., D.L., B.Y., S.C., D.G., L.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Laiyuan Wang
- Key Laboratory of Cardiovascular Epidemiology and Department of Epidemiology, State Key Laboratory of Cardiovascular Disease (X.R., H.Z., K.D., X.N., D.L., B.Y., S.C., D.G., L.W.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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You GR, Chang JT, Li YL, Huang CW, Tsai YL, Fan KH, Kang CJ, Huang SF, Chang PH, Cheng AJ. MYH9 Facilitates Cell Invasion and Radioresistance in Head and Neck Cancer via Modulation of Cellular ROS Levels by Activating the MAPK-Nrf2-GCLC Pathway. Cells 2022; 11:cells11182855. [PMID: 36139430 PMCID: PMC9497050 DOI: 10.3390/cells11182855] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 09/06/2022] [Accepted: 09/09/2022] [Indexed: 12/14/2022] Open
Abstract
The MYH9 (Myosin heavy chain 9), an architecture component of the actomyosin cytoskeleton, has been reported to be dysregulated in several types of cancers. However, how this molecule contributes to cancer development is still obscure. This study deciphered the molecular function of MYH9 in head and neck cancer (HNC). Cellular methods included clonogenic survival, wound-healing migration, and Matrigel invasion assays. Molecular techniques included RT-qPCR, western blot, luciferase reporter assays, and flow cytometry. Clinical association studies were undertaken by TCGA data mining, Spearman correlation, and Kaplan-Meier survival analysis. We found that MYH9 was overexpressed in tumors and associated with poor prognosis in HNC patients. MYH9 promoted cell motility along with the modulation of the extracellular matrix (fibronectin, ITGA6, fascin, vimentin, MMPs). Also, MYH9 contributed to radioresistance and was related to the expression of anti-apoptotic and DNA repairing molecules (XIAP, MCL1, BCL2L1, ATM, RAD50, and NBN). Mechanically, MYH9 suppressed cellular ROS levels, which were achieved by activating the pan-MAPK signaling molecules (Erk, p38, and JNK), the induction of Nrf2 transcriptional activity, and the up-regulation of antioxidant enzymes (GCLC, GCLM, GPX2). The antioxidant enzyme GCLC was further demonstrated to facilitate cell invasion and radioresistance in HNC cells. Thus, MYH9 exerts malignant functions in HNC by regulating cellular ROS levels via activating the MAPK-Nrf2-GCLC signaling pathway. As MYH9 contributes to radioresistance and metastasis, this molecule may serve as a prognostic biomarker for clinical application. Furthermore, an in vivo study is emergent to support the therapeutic potential of targeting MYH9 to better manage refractory cancers.
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Affiliation(s)
- Guo-Rung You
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Joseph T. Chang
- Department of Radiation Oncology, Chang Gung Memorial Hospital-Linkou, Taoyuan 33305, Taiwan
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Yan-Liang Li
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Chi-Wei Huang
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Yu-Liang Tsai
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Kang-Hsing Fan
- Department of Radiation Oncology, Chang Gung Memorial Hospital-Linkou, Taoyuan 33305, Taiwan
- Department of Radiation Oncology, New Taipei Municipal TuCheng Hospital, New Taipei City 236017, Taiwan
- Department of Medical Imaging and Radiological Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
| | - Chung-Jan Kang
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Otorhinolaryngology, Chang Gung Memorial Hospital-LinKou, Taoyuan 33305, Taiwan
| | - Shiang-Fu Huang
- School of Medicine, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Otorhinolaryngology, Chang Gung Memorial Hospital-LinKou, Taoyuan 33305, Taiwan
| | - Po-Hung Chang
- Department of Otorhinolaryngology, Chang Gung Memorial Hospital-LinKou, Taoyuan 33305, Taiwan
| | - Ann-Joy Cheng
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Department of Radiation Oncology, Chang Gung Memorial Hospital-Linkou, Taoyuan 33305, Taiwan
- Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan
- Correspondence: ; Tel.: +886-3-2118-800
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30
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Wang B, Li H, Li Z, Wang B, Zhang H, Zhang B, Luo H. Integrative network analysis revealed the molecular function of folic acid on immunological enhancement in a sheep model. Front Immunol 2022; 13:913854. [PMID: 36032143 PMCID: PMC9412826 DOI: 10.3389/fimmu.2022.913854] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
We previously observed the beneficial role of folic acid supplemented from maternal or offspring diet on lamb growth performance and immunity. Twenty-four Hu lambs from four groups (mother received folic acid or not, offspring received folic acid or not) were used in the current study, which was conducted consecutively to elucidate the molecular regulatory mechanisms of folic acid in lambs by analyzing blood metabolome, liver transcriptome, and muscle transcriptome. Serum metabolomics analysis showed that L-homocitrulline, hyodeoxycholic acid, 9-Hpode, palmitaldehyde, N-oleoyl glycine, hexadecanedioic acid, xylose, 1,7-dimethylxanthine, nicotinamide, acetyl-N-formyl-5-methoxykynurenamine, N6-succinyl adenosine, 11-cis-retinol, 18-hydroxycorticosterone, and 2-acetylfuran were down-regulated and methylisobutyrate was up-regulated by the feeding of folic acid from maternal and/or offspring diets. Meanwhile, folic acid increased the abundances of S100A12 and IRF6 but decreased TMEM25 in the liver. In the muscle, RBBP9, CALCR, PPP1R3D, UCP3, FBXL4, CMBL, and MTFR2 were up-regulated, CYP26B1 and MYH9 were down-regulated by the feeding of folic acid. The pathways of bile secretion, biosynthesis of unsaturated fatty acids, linoleic acid metabolism, and herpes simplex virus 1 infection were changed by folic acid in blood, liver, or muscle. Further integrated analysis revealed potential interactions among the liver, blood, and muscle, and the circulating metabolites, hub gene, and pathways, which might be the predominant acting targets of folic acid in animals. These findings provide fundamental information on the beneficial function of folic acid no matter from maternal or offspring, in regulating animal lipid metabolism and immune enhancement, providing a theoretical basis for the use of folic acid from the view of animal health care.
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Defective VWF secretion due to the expression of MYH9-RD E1841K mutant in endothelial cells disrupts hemostasis. Blood Adv 2022; 6:4537-4552. [PMID: 35764499 DOI: 10.1182/bloodadvances.2022008011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 06/08/2022] [Indexed: 11/20/2022] Open
Abstract
Mutations in MYH9, the gene encoding the heavy chain of non-muscle myosin IIa (NMII-A), cause MYH9-related disease (MYH9-RD) that is an autosomal-dominant thrombocytopenia with bleeding tendency. Previously, we showed that NMII-A in endothelial cells (ECs) is critical for hemostasis via regulating von Willebrand factor (VWF) release from Weibel-Palade bodies (WPBs). The aim of this study was to determine the role of the expression of MYH9 mutants in ECs in the pathogenesis of the MYH9-RD bleeding symptom. First, we expressed the 5 most common NMII-A mutants in ECs, and found that E1841K mutant-expressing ECs secreted less VWF than the controls in response to a cAMP signaling agonist. Then, we generated 2 knockin mouse lines, one with Myh9 E1841K in ECs and the other in megakaryocytes. Endothelium-specific E1841K mice exhibited impaired cAMP-induced VWF release and a prolonged bleeding time with normal platelets, while megakaryocyte-specific E1841K mice exhibited macrothrombocytopenia and a prolonged bleeding time with normal VWF release. Finally, we present mechanistic findings that E1841K mutation not only interferes with S1943 phosphorylation and impairs the peripheral distribution of Rab27a positive WPBs in ECs under quiescent condition, but also interferes with S1916 phosphorylation by disrupting the interaction with zyxin and CKIIα, and reduces actin framework formation around WPBs and subsequent VWF secretion under the stimulation by a cAMP agonist. Altogether, our results suggest that impaired cAMP-induced endothelial VWF secretion by E1841K mutant expression may contribute to the MYH9-RD bleeding phenotype.
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An Q, Dong Y, Cao Y, Pan X, Xue Y, Zhou Y, Zhang Y, Ma F. Myh9 Plays an Essential Role in the Survival and Maintenance of Hematopoietic Stem/Progenitor Cells. Cells 2022; 11:cells11121865. [PMID: 35740994 PMCID: PMC9221478 DOI: 10.3390/cells11121865] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 06/03/2022] [Accepted: 06/06/2022] [Indexed: 02/05/2023] Open
Abstract
Myosin heavy chain 9 (MYH9) gene encodes a protein named non-muscle heavy chain IIA (NMHC IIA), interacting with actin and participating in various biological processes. Mutations in MYH9 cause an array of autosomal dominant disorders, known as MYH9-related diseases (MYH9-RD). However, the role of MYH9 in normal hematopoiesis remains largely unexplored. By using Mx1-cre Myh9 conditional knockout mice, we established an inducible system to precisely inactivate Myh9 function in hematopoietic cells in vivo. The results showed that deletion of Myh9 led to severe defects in hematopoiesis, characterized by pancytopenia, drastic decreases of hematopoietic stem/progenitor cells (HSPC), and bone marrow failure, causing early lethality in mice. The defect in hematopoiesis caused by Myh9 ablation is cell autonomous. In addition, Myh9 deletion impairs HSPC repopulation capacity and increases apoptosis. RNA sequencing results revealed significant alterations in the expression of genes related to HSC self-renewal and maintenance, while multiple signal pathways were also involved, including genes for HSC and myeloid cell development, intrinsic apoptosis, targets of mTOR signaling, and maturity of hematopoietic cells. Our present study suggests an essential role for Myh9 in the survival and maintenance of HSPC in normal hematopoiesis.
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Affiliation(s)
- Quanming An
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Science & Peking Union Medical College (CAMS & PUMC), Chengdu 610025, China; (Q.A.); (Y.D.); (X.P.); (Y.X.); (Y.Z.)
| | - Yong Dong
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Science & Peking Union Medical College (CAMS & PUMC), Chengdu 610025, China; (Q.A.); (Y.D.); (X.P.); (Y.X.); (Y.Z.)
| | - Yang Cao
- Institute of Molecular Medicine, School of Future Technology, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China;
| | - Xu Pan
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Science & Peking Union Medical College (CAMS & PUMC), Chengdu 610025, China; (Q.A.); (Y.D.); (X.P.); (Y.X.); (Y.Z.)
| | - Yuan Xue
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Science & Peking Union Medical College (CAMS & PUMC), Chengdu 610025, China; (Q.A.); (Y.D.); (X.P.); (Y.X.); (Y.Z.)
| | - Ya Zhou
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Science & Peking Union Medical College (CAMS & PUMC), Chengdu 610025, China; (Q.A.); (Y.D.); (X.P.); (Y.X.); (Y.Z.)
| | - Yonggang Zhang
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Science & Peking Union Medical College (CAMS & PUMC), Chengdu 610025, China; (Q.A.); (Y.D.); (X.P.); (Y.X.); (Y.Z.)
- Correspondence: (Y.Z.); (F.M.)
| | - Feng Ma
- Center for Stem Cell Research and Application, Institute of Blood Transfusion, Chinese Academy of Medical Science & Peking Union Medical College (CAMS & PUMC), Chengdu 610025, China; (Q.A.); (Y.D.); (X.P.); (Y.X.); (Y.Z.)
- Correspondence: (Y.Z.); (F.M.)
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Sun J, Guo Y, Chen T, Jin T, Ma L, Ai L, Guo J, Niu Z, Yang R, Wang Q, Yu X, Gao H, Zhang Y, Su W, Song X, Ji W, Zhang Q, Huang M, Fan X, Du Z, Liang H. Systematic analyses identify the anti-fibrotic role of lncRNA TP53TG1 in IPF. Cell Death Dis 2022; 13:525. [PMID: 35661695 PMCID: PMC9166247 DOI: 10.1038/s41419-022-04975-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Revised: 05/18/2022] [Accepted: 05/25/2022] [Indexed: 01/21/2023]
Abstract
Long non-coding RNA (lncRNA) was reported to be a critical regulator of cellular homeostasis, but poorly understood in idiopathic pulmonary fibrosis (IPF). Here, we systematically identified a crucial lncRNA, p53-induced long non-coding RNA TP53 target 1 (TP53TG1), which was the dysregulated hub gene in IPF regulatory network and one of the top degree genes and down-regulated in IPF-drived fibroblasts. Functional experiments revealed that overexpression of TP53TG1 attenuated the increased expression of fibronectin 1 (Fn1), Collagen 1α1, Collagen 3α1, ACTA2 mRNA, Fn1, and Collagen I protein level, excessive fibroblasts proliferation, migration and differentiation induced by TGF-β1 in MRC-5 as well as PMLFs. In vivo assays identified that forced expression of TP53TG1 by adeno-associated virus 5 (AAV5) not only prevented BLM-induced experimental fibrosis but also reversed established lung fibrosis in the murine model. Mechanistically, TP53TG1 was found to bind to amount of tight junction proteins. Importantly, we found that TP53TG1 binds to the Myosin Heavy Chain 9 (MYH9) to inhibit its protein expression and thus the MYH9-mediated activation of fibroblasts. Collectively, we identified the TP53TG1 as a master suppressor of fibroblast activation and IPF, which could be a potential hub for targeting treatment of the disease.
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Affiliation(s)
- Jian Sun
- grid.258164.c0000 0004 1790 3548Zhuhai People’s Hospital, Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Hospital Affiliated With Jinan University, Jinan University, Zhuhai, 519000 Guangdong China ,grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Yingying Guo
- grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Tingting Chen
- grid.410736.70000 0001 2204 9268Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081 China
| | - Tongzhu Jin
- grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Lu Ma
- grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Liqiang Ai
- grid.410736.70000 0001 2204 9268Department of Systems Biology, College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, 150081 China
| | - Jiayu Guo
- grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Zhihui Niu
- grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Ruoxuan Yang
- grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Qianqian Wang
- grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Xiaojiang Yu
- grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Huiying Gao
- grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Yuhan Zhang
- grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Wei Su
- grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Xiaoying Song
- grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Weihang Ji
- grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Qing Zhang
- grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Mengqin Huang
- grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China
| | - Xingxing Fan
- grid.259384.10000 0000 8945 4455State Key Laboratory of Quality Research in Chinese Medicine/Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau (SAR), China
| | - Zhimin Du
- grid.258164.c0000 0004 1790 3548Zhuhai People’s Hospital, Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Hospital Affiliated With Jinan University, Jinan University, Zhuhai, 519000 Guangdong China ,grid.410736.70000 0001 2204 9268Institute of Clinical Pharmacy, the 2nd Affiliated Hospital, Harbin Medical University, Harbin, 150081 China
| | - Haihai Liang
- grid.258164.c0000 0004 1790 3548Zhuhai People’s Hospital, Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai Hospital Affiliated With Jinan University, Jinan University, Zhuhai, 519000 Guangdong China ,grid.410736.70000 0001 2204 9268Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, 150081 China ,Research Unit of Noninfectious Chronic Diseases in Frigid Zone (2019RU070), Chinese Academy of Medical Sciences, Harbin, 150081 China
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Ham H, Medlyn M, Billadeau DD. Locked and Loaded: Mechanisms Regulating Natural Killer Cell Lytic Granule Biogenesis and Release. Front Immunol 2022; 13:871106. [PMID: 35558071 PMCID: PMC9088006 DOI: 10.3389/fimmu.2022.871106] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 03/29/2022] [Indexed: 11/22/2022] Open
Abstract
NK cell-mediated cytotoxicity is a critical element of our immune system required for protection from microbial infections and cancer. NK cells bind to and eliminate infected or cancerous cells via direct secretion of cytotoxic molecules toward the bound target cells. In this review, we summarize the current understanding of the molecular regulations of NK cell cytotoxicity, focusing on lytic granule development and degranulation processes. NK cells synthesize apoptosis-inducing proteins and package them into specialized organelles known as lytic granules (LGs). Upon activation of NK cells, LGs converge with the microtubule organizing center through dynein-dependent movement along microtubules, ultimately polarizing to the cytotoxic synapse where they subsequently fuse with the NK plasma membrane. From LGs biogenesis to degranulation, NK cells utilize several strategies to protect themselves from their own cytotoxic molecules. Additionally, molecular pathways that enable NK cells to perform serial killing are beginning to be elucidated. These advances in the understanding of the molecular pathways behind NK cell cytotoxicity will be important to not only improve current NK cell-based anti-cancer therapies but also to support the discovery of additional therapeutic opportunities.
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Affiliation(s)
- Hyoungjun Ham
- Division of Oncology Research, Mayo Clinic, Rochester, MN, United States
| | - Michael Medlyn
- Department of Immunology College of Medicine, Mayo Clinic, Rochester, MN, United States
| | - Daniel D Billadeau
- Division of Oncology Research, Mayo Clinic, Rochester, MN, United States.,Department of Immunology College of Medicine, Mayo Clinic, Rochester, MN, United States
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35
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Allen A, Maddala R, Eldawy C, Rao PV. Mechanical Load and Piezo1 Channel Regulated Myosin II Activity in Mouse Lenses. Int J Mol Sci 2022; 23:4710. [PMID: 35563101 PMCID: PMC9105872 DOI: 10.3390/ijms23094710] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 04/13/2022] [Accepted: 04/19/2022] [Indexed: 02/01/2023] Open
Abstract
The cytoarchitecture and tensile characteristics of ocular lenses play a crucial role in maintaining their transparency and deformability, respectively, which are properties required for the light focusing function of ocular lens. Calcium-dependent myosin-II-regulated contractile characteristics and mechanosensitive ion channel activities are presumed to influence lens shape change and clarity. Here, we investigated the effects of load-induced force and the activity of Piezo channels on mouse lens myosin II activity. Expression of the Piezo1 channel was evident in the mouse lens based on immunoblot and immufluorescence analyses and with the use of a Piezo1-tdT transgenic mouse model. Under ex vivo conditions, change in lens shape induced by the load decreased myosin light chain (MLC) phosphorylation. While the activation of Piezo1 by Yoda1 for one hour led to an increase in the levels of phosphorylated MLC, Yoda1 treatment for an extended period led to opacification in association with increased calpain activity and degradation of membrane proteins in ex vivo mouse lenses. In contrast, inhibition of Piezo1 by GsMTx4 decreased MLC phosphorylation but did not affect the lens tensile properties. This exploratory study reveals a role for the mechanical load and Piezo1 channel activity in the regulation of myosin II activity in lens, which could be relevant to lens shape change during accommodation.
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Affiliation(s)
- Ariana Allen
- Department of Ophthalmology, Duke University School of Medicine, Durham, NC 27710, USA; (A.A.); (R.M.); (C.E.)
| | - Rupalatha Maddala
- Department of Ophthalmology, Duke University School of Medicine, Durham, NC 27710, USA; (A.A.); (R.M.); (C.E.)
| | - Camelia Eldawy
- Department of Ophthalmology, Duke University School of Medicine, Durham, NC 27710, USA; (A.A.); (R.M.); (C.E.)
| | - Ponugoti Vasantha Rao
- Department of Ophthalmology, Duke University School of Medicine, Durham, NC 27710, USA; (A.A.); (R.M.); (C.E.)
- Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC 27710, USA
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Lv Z, Ding Y, Cao W, Wang S, Gao K. Role of RHO family interacting cell polarization regulators (RIPORs) in health and disease: Recent advances and prospects. Int J Biol Sci 2022; 18:800-808. [PMID: 35002526 PMCID: PMC8741841 DOI: 10.7150/ijbs.65457] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Accepted: 11/27/2021] [Indexed: 12/11/2022] Open
Abstract
The RHO GTPase family has been suggested to play critical roles in cell growth, migration, and polarization. Regulators and effectors of RHO GTPases have been extensively explored in recent years. However, little attention has been given to RHO family interacting cell polarization regulators (RIPORs), a recently discovered protein family of RHO regulators. RIPOR proteins, namely, RIPOR1-3, bind directly to RHO proteins (A, B and C) via a RHO-binding motif and exert suppressive effects on RHO activity, thereby negatively influencing RHO-regulated cellular functions. In addition, RIPORs are phosphorylated by upstream protein kinases under chemokine stimulation, and this phosphorylation affects not only their subcellular localization but also their interaction with RHO proteins, altering the activation of RHO downstream targets and ultimately impacting cell polarity and migration. In this review, we provide an overview of recent studies on the function of RIPOR proteins in regulating RHO-dependent directional movement in immune responses and other pathophysiological functions.
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Affiliation(s)
- Zeheng Lv
- Department of Clinical Laboratory, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Yan Ding
- Department of Clinical Laboratory, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Wenxin Cao
- Department of Clinical Laboratory, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Shuyun Wang
- Department of Breast Surgery, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
| | - Kun Gao
- Department of Clinical Laboratory, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China
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Li S, Ding C, Guo Y, Zhang Y, Wang H, Sun X, Zhang J, Cui Z, Chen J. Mechanotransduction Regulates Reprogramming Enhancement in Adherent 3D Keratocyte Cultures. Front Bioeng Biotechnol 2021; 9:709488. [PMID: 34568299 PMCID: PMC8460903 DOI: 10.3389/fbioe.2021.709488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/27/2021] [Indexed: 11/18/2022] Open
Abstract
Suspended spheroid culture using ultralow attachment plates (ULAPs) is reported to effect corneal fibroblast reprogramming. Polydimethylsiloxane (PDMS), with hydrophobic and soft substrate properties, facilitates adherent spheroid formation that promotes cellular physical reprogramming into stem-like cells without using transcription factors. However, it is still unknown whether the biophysical properties of PDMS have the same effect on adult human corneal keratocyte reprogramming. Here, PDMS and essential 8 (E8) medium were utilized to culture keratocyte spheroids and fibroblast spheroids, and the reprogramming results were compared. We provide insights into the probable mechanisms of the PDMS effect on spheroids. qPCR analysis showed that the expression of some stem cell marker genes (OCT4, NANOG, SOX2, KLF4, CMYC, ABCG2 and PAX6) was significantly greater in keratocyte spheroids than in fibroblast spheroids. The endogenous level of stemness transcription factors (OCT4, NANOG, SOX2, KLF4 and CMYC) was higher in keratocytes than in fibroblasts. Immunofluorescence staining revealed Klf4, Nanog, Sox2, ABCG2 and Pax6 were positively stained in adherent 3D spheroids but weakly or negatively stained in adherent 2D cells. Furthermore, OCT4, NANOG, SOX2, KLF4, HNK1, ABCG2 and PAX6 gene expression was significantly higher in adherent 3D spheroids than in adherent 2D cells. Meanwhile, SOX2, ABCG2 and PAX6 were more upregulated in adherent 3D spheroids than in suspended 3D spheroids. The RNA-seq analysis suggested that regulation of the actin cytoskeleton, TGFβ/BMP and HIF-1 signaling pathways induced changes in mechanotransduction, the mesenchymal-to-epithelial transition and hypoxia, which might be responsible for the effect of PDMS on facilitating reprogramming. In conclusion, compared to corneal fibroblasts, keratocytes were more susceptible to reprogramming due to higher levels of endogenous stemness transcription factors. Spheroid culture of keratocytes using PDMS had a positive impact on promoting the expression of some stem cell markers. PDMS, as a substrate to form spheroids, was better able to promote reprogramming than ULAPs. These results indicated that the physiological cells and culture conditions herein enhance reprogramming. Therefore, adherent spheroid culture of keratocytes using PDMS is a promising strategy to more safely promote reprogramming, suggesting its potential application for developing clinical implants in tissue engineering and regenerative medicine.
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Affiliation(s)
- Shenyang Li
- Aier School of Ophthalmology, Central South University, Changsha, China
| | | | - Yonglong Guo
- Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China
| | - Yanan Zhang
- Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China
| | - Hao Wang
- Aier School of Ophthalmology, Central South University, Changsha, China
| | - Xihao Sun
- Aier School of Ophthalmology, Central South University, Changsha, China
| | - Jun Zhang
- Key Laboratory of Optoelectronic Information and Sensing Technologies of Guangdong Higher Educational Institutes, Jinan University, Guangzhou, China
| | - Zekai Cui
- Aier School of Ophthalmology, Central South University, Changsha, China.,Aier Eye Institute, Changsha, China
| | - Jiansu Chen
- Aier School of Ophthalmology, Central South University, Changsha, China.,Aier Eye Institute, Changsha, China.,Key Laboratory for Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China
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OC-STAMP Overexpression Drives Lung Alveolar Epithelial Cell Type II Senescence in Silicosis. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:4158495. [PMID: 34426759 PMCID: PMC8380176 DOI: 10.1155/2021/4158495] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 07/27/2021] [Indexed: 02/05/2023]
Abstract
Cellular senescence has been considered an important driver of many chronic lung diseases. However, the specific mechanism of cellular senescence in silicosis is still unknown. In the present study, silicotic rats and osteoclast stimulatory transmembrane protein (Ocstamp) overexpression of MLE-12 cells were used to explore the mechanism of OC-STAMP in cellular senescence in alveolar epithelial cell type II (AEC2). We found an increasing level of OC-STAMP in AEC2 of silicotic rats. Overexpression of Ocstamp in MLE-12 cells promoted epithelial-mesenchymal transition (EMT), endoplasmic reticulum (ER) stress, and cellular senescence. Myosin heavy chain 9 (MYH9) was a potential interacting protein of OC-STAMP. Knockdown of Ocstamp or Myh9 inhibited cellular senescence in MLE-12 cells transfected with pcmv6-Ocstamp. Treatment with 4-phenylbutyrate (4-PBA) to inhibit ER stress also attenuated cellular senescence in vitro or in vivo. In conclusion, OC-STAMP promotes cellular senescence in AEC2 in silicosis.
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Garrido-Casado M, Asensio-Juárez G, Vicente-Manzanares M. Nonmuscle Myosin II Regulation Directs Its Multiple Roles in Cell Migration and Division. Annu Rev Cell Dev Biol 2021; 37:285-310. [PMID: 34314591 DOI: 10.1146/annurev-cellbio-042721-105528] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Nonmuscle myosin II (NMII) is a multimeric protein complex that generates most mechanical force in eukaryotic cells. NMII function is controlled at three main levels. The first level includes events that trigger conformational changes that extend the complex to enable its assembly into filaments. The second level controls the ATPase activity of the complex and its binding to microfilaments in extended NMII filaments. The third level includes events that modulate the stability and contractility of the filaments. They all work in concert to finely control force generation inside cells. NMII is a common endpoint of mechanochemical signaling pathways that control cellular responses to physical and chemical extracellular cues. Specific phosphorylations modulate NMII activation in a context-dependent manner. A few kinases control these phosphorylations in a spatially, temporally, and lineage-restricted fashion, enabling functional adaptability to the cellular microenvironment. Here, we review mechanisms that control NMII activity in the context of cell migration and division. Expected final online publication date for the Annual Review of Cell and Developmental Biology, Volume 37 is October 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Marina Garrido-Casado
- Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas, University of Salamanca, 37007 Salamanca, Spain;
| | - Gloria Asensio-Juárez
- Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas, University of Salamanca, 37007 Salamanca, Spain;
| | - Miguel Vicente-Manzanares
- Molecular Mechanisms Program, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas, University of Salamanca, 37007 Salamanca, Spain;
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Soriano O, Alcón-Pérez M, Vicente-Manzanares M, Castellano E. The Crossroads between RAS and RHO Signaling Pathways in Cellular Transformation, Motility and Contraction. Genes (Basel) 2021; 12:genes12060819. [PMID: 34071831 PMCID: PMC8229961 DOI: 10.3390/genes12060819] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 05/25/2021] [Accepted: 05/26/2021] [Indexed: 02/07/2023] Open
Abstract
Ras and Rho proteins are GTP-regulated molecular switches that control multiple signaling pathways in eukaryotic cells. Ras was among the first identified oncogenes, and it appears mutated in many forms of human cancer. It mainly promotes proliferation and survival through the MAPK pathway and the PI3K/AKT pathways, respectively. However, the myriad proteins close to the plasma membrane that activate or inhibit Ras make it a major regulator of many apparently unrelated pathways. On the other hand, Rho is weakly oncogenic by itself, but it critically regulates microfilament dynamics; that is, actin polymerization, disassembly and contraction. Polymerization is driven mainly by the Arp2/3 complex and formins, whereas contraction depends on myosin mini-filament assembly and activity. These two pathways intersect at numerous points: from Ras-dependent triggering of Rho activators, some of which act through PI3K, to mechanical feedback driven by actomyosin action. Here, we describe the main points of connection between the Ras and Rho pathways as they coordinately drive oncogenic transformation. We emphasize the biochemical crosstalk that drives actomyosin contraction driven by Ras in a Rho-dependent manner. We also describe possible routes of mechanical feedback through which myosin II activation may control Ras/Rho activation.
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Affiliation(s)
- Olga Soriano
- Tumor Biophysics Laboratory, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, 37007 Salamanca, Spain;
| | - Marta Alcón-Pérez
- Tumour-Stroma Signalling Laboratory, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, 37007 Salamanca, Spain;
| | - Miguel Vicente-Manzanares
- Tumor Biophysics Laboratory, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, 37007 Salamanca, Spain;
- Correspondence: (M.V.-M.); (E.C.)
| | - Esther Castellano
- Tumour-Stroma Signalling Laboratory, Centro de Investigación del Cáncer and Instituto de Biología Molecular y Celular del Cáncer, Consejo Superior de Investigaciones Científicas (CSIC)-University of Salamanca, 37007 Salamanca, Spain;
- Correspondence: (M.V.-M.); (E.C.)
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Wang YW, Wu YH, Zhang JZ, Tang JH, Fan RP, Li F, Yu BY, Kou JP, Zhang YY. Ruscogenin attenuates particulate matter-induced acute lung injury in mice via protecting pulmonary endothelial barrier and inhibiting TLR4 signaling pathway. Acta Pharmacol Sin 2021; 42:726-734. [PMID: 32855531 PMCID: PMC8114925 DOI: 10.1038/s41401-020-00502-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Accepted: 07/31/2020] [Indexed: 12/15/2022]
Abstract
The inhalation of particulate matter (PM) is closely related to respiratory damage, including acute lung injury (ALI), characterized by inflammatory fluid edema and disturbed alveolar-capillary permeability. Ruscogenin (RUS), the main active ingredient in the traditional Chinese medicine Ophiopogonis japonicus, has been found to exhibit anti-inflammatory activity and rescue LPS-induced ALI. In this study, we investigated whether and how RUS exerted therapeutic effects on PM-induced ALI. RUS (0.1, 0.3, 1 mg·kg-1·d-1) was orally administered to mice prior to or after intratracheal instillation of PM suspension (50 mg/kg). We showed that RUS administration either prior to or after PM challenge significantly attenuated PM-induced pathological injury, lung edema, vascular leakage and VE-cadherin expression in lung tissue. RUS administration significantly decreased the levels of cytokines IL-6 and IL-1β, as well as the levels of NO and MPO in both bronchoalveolar lavage fluid (BALF) and serum. RUS administration dose-dependently suppressed the phosphorylation of NF-κB p65 and the expression of TLR4 and MyD88 in lung tissue. Furthermore, TLR4 knockout partly diminished PM-induced lung injury, and abolished the protective effects of RUS in PM-instilled mice. In conclusion, RUS effectively alleviates PM-induced ALI probably by inhibition of vascular leakage and TLR4/MyD88 signaling. TLR4 might be crucial for PM to initiate pulmonary lesion and for RUS to exert efficacy against PM-induced lung injury.
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Affiliation(s)
- Yu-Wei Wang
- State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Yun-Hao Wu
- State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Jia-Zhi Zhang
- State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Jia-Hui Tang
- State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Rui-Ping Fan
- State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Fang Li
- State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Bo-Yang Yu
- State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China
| | - Jun-Ping Kou
- State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
| | - Yuan-Yuan Zhang
- State Key Laboratory of Natural Products, Jiangsu Key Laboratory of TCM Evaluation and Translational Research, Department of Pharmacology of Chinese Material Medica, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
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Naydenov NG, Lechuga S, Huang EH, Ivanov AI. Myosin Motors: Novel Regulators and Therapeutic Targets in Colorectal Cancer. Cancers (Basel) 2021; 13:741. [PMID: 33670106 PMCID: PMC7916823 DOI: 10.3390/cancers13040741] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 02/06/2021] [Accepted: 02/08/2021] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) remains the third most common cause of cancer and the second most common cause of cancer deaths worldwide. Clinicians are largely faced with advanced and metastatic disease for which few interventions are available. One poorly understood aspect of CRC involves altered organization of the actin cytoskeleton, especially at the metastatic stage of the disease. Myosin motors are crucial regulators of actin cytoskeletal architecture and remodeling. They act as mechanosensors of the tumor environments and control key cellular processes linked to oncogenesis, including cell division, extracellular matrix adhesion and tissue invasion. Different myosins play either oncogenic or tumor suppressor roles in breast, lung and prostate cancer; however, little is known about their functions in CRC. This review focuses on the functional roles of myosins in colon cancer development. We discuss the most studied class of myosins, class II (conventional) myosins, as well as several classes (I, V, VI, X and XVIII) of unconventional myosins that have been linked to CRC development. Altered expression and mutations of these motors in clinical tumor samples and their roles in CRC growth and metastasis are described. We also evaluate the potential of using small molecular modulators of myosin activity to develop novel anticancer therapies.
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Affiliation(s)
- Nayden G. Naydenov
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (N.G.N.); (S.L.)
| | - Susana Lechuga
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (N.G.N.); (S.L.)
| | - Emina H. Huang
- Departments of Cancer Biology and Colorectal Surgery, Cleveland Clinic Foundation, Cleveland, OH 44195, USA;
| | - Andrei I. Ivanov
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA; (N.G.N.); (S.L.)
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Non-Muscle Myosin 2A (NM2A): Structure, Regulation and Function. Cells 2020; 9:cells9071590. [PMID: 32630196 PMCID: PMC7408548 DOI: 10.3390/cells9071590] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 06/25/2020] [Accepted: 06/29/2020] [Indexed: 12/30/2022] Open
Abstract
Non-muscle myosin 2A (NM2A) is a motor cytoskeletal enzyme with crucial importance from the early stages of development until adulthood. Due to its capacity to convert chemical energy into force, NM2A powers the contraction of the actomyosin cytoskeleton, required for proper cell division, adhesion and migration, among other cellular functions. Although NM2A has been extensively studied, new findings revealed that a lot remains to be discovered concerning its spatiotemporal regulation in the intracellular environment. In recent years, new functions were attributed to NM2A and its activity was associated to a plethora of illnesses, including neurological disorders and infectious diseases. Here, we provide a concise overview on the current knowledge regarding the structure, the function and the regulation of NM2A. In addition, we recapitulate NM2A-associated diseases and discuss its potential as a therapeutic target.
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