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Li D, Ma Q. Ubiquitin-specific protease: an emerging key player in cardiomyopathy. Cell Commun Signal 2025; 23:143. [PMID: 40102846 PMCID: PMC11921692 DOI: 10.1186/s12964-025-02123-0] [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: 12/19/2024] [Accepted: 02/23/2025] [Indexed: 03/20/2025] Open
Abstract
Protein quality control (PQC) plays a vital role in maintaining normal heart function, as cardiomyocytes are relatively sensitive to misfolded or damaged proteins, which tend to accumulate under pathological conditions. Ubiquitin-specific protease (USP) is the largest deubiquitinating enzyme family and a key component of the ubiquitin proteasome system (UPS), which is a non-lysosomal protein degradation machinery to mediate PQC in cells. USPs regulate the stability or activity of the target proteins that involve intracellular signaling, transcriptional control of inflammation, antioxidation, and cell growth. Recent studies demonstrate that the USPs can regulate fibrosis, lipid metabolism, glucose homeostasis, hypertrophic response, post-ischemic recovery and cell death such as apoptosis and ferroptosis in cardiomyocytes. Since myocardial cell loss is an important component of cardiomyopathy, therefore, these findings suggest that the UPSs play emerging roles in cardiomyopathy. This review briefly summarizes recent literature on the regulatory roles of USPs in the occurrence and development of cardiomyopathy, giving us new insights into the molecular mechanisms of USPs in different cardiomyopathy and potential preventive strategies for cardiomyopathy.
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Affiliation(s)
- Danlei Li
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan Province, China
| | - Qilin Ma
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan Province, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan Province, China.
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Rezaei S, Timani KA, Liu Y, He JJ. Ectopic USP15 expression inhibits HIV-1 transcription involving changes in YY1 deubiquitination and stability. Front Cell Infect Microbiol 2024; 14:1371655. [PMID: 39624264 PMCID: PMC11609158 DOI: 10.3389/fcimb.2024.1371655] [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: 01/16/2024] [Accepted: 10/21/2024] [Indexed: 01/13/2025] Open
Abstract
Introduction Protein homeostasis is maintained by the opposing action of ubiquitin ligase and deubiquitinase, two important components of the ubiquitin-proteasome pathway, and contributes to both normal physiological and pathophysiological processes. The current study aims to delineate the roles of ubiquitin-specific protease 15 (USP15), a member of the largest deubiquitinase family, in HIV-1 gene expression and replication. Methods We took advantage of highly selective and specific ubiquitin variants (UbV), which were recently designed and developed for USP15, and ascertained the inhibitory effects of USP15 on HIV-1 gene expression and production by transfection and Western blotting. We also used real-time RT-PCR, transcription factor profiling, subcellular fractionation, immunoprecipitation followed by Western blotting to determine the transcription factors involved and the underlying molecular mechanisms. Results We first confirmed the specificity of USP15-mediated HIV-1 gene expression and virus production. We then showed that the inhibition of HIV-1 production by USP15 occurred at the transcription level, associated with an increased protein level of YY1, a known HIV-1 transcription repressor. Moreover, we demonstrated that USP15 regulated YY1 deubiquitination and stability. Lastly, we demonstrated that YY1 siRNA knockdown significantly diminished the inhibition of USP15 on HIV-1 gene expression and virus production. Conclusion These findings together demonstrate that stabilization of YY1 protein by USP15 deubiquitinating activity contributes to USP15-mediated inhibition of HIV-1 transcription and may help the development of USP15-specific UbV inhibitors as an anti-HIV strategy.
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Affiliation(s)
- Sahar Rezaei
- Department of Microbiology and Immunology, Rosalind Franklin University, Chicago Medical School, North Chicago, IL, United States
- Center for Cancer Cell Biology, Immunology and Infection, Rosalind Franklin University, North Chicago, IL, United States
- School of Graduate and Postdoctoral Studies, Rosalind Franklin University, North Chicago, IL, United States
| | - Khalid A. Timani
- Department of Microbiology and Immunology, Rosalind Franklin University, Chicago Medical School, North Chicago, IL, United States
- Center for Cancer Cell Biology, Immunology and Infection, Rosalind Franklin University, North Chicago, IL, United States
- School of Graduate and Postdoctoral Studies, Rosalind Franklin University, North Chicago, IL, United States
| | - Ying Liu
- Department of Microbiology and Immunology, Rosalind Franklin University, Chicago Medical School, North Chicago, IL, United States
- Center for Cancer Cell Biology, Immunology and Infection, Rosalind Franklin University, North Chicago, IL, United States
- School of Graduate and Postdoctoral Studies, Rosalind Franklin University, North Chicago, IL, United States
| | - Johnny J. He
- Department of Microbiology and Immunology, Rosalind Franklin University, Chicago Medical School, North Chicago, IL, United States
- Center for Cancer Cell Biology, Immunology and Infection, Rosalind Franklin University, North Chicago, IL, United States
- School of Graduate and Postdoctoral Studies, Rosalind Franklin University, North Chicago, IL, United States
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Häussler U, Neres J, Vandenplas C, Eykens C, Kadiu I, Schramm C, Fleurance R, Stanley P, Godard P, de Mot L, van Eyll J, Knobeloch KP, Haas CA, Dedeurwaerdere S. Downregulation of Ubiquitin-Specific Protease 15 (USP15) Does Not Provide Therapeutic Benefit in Experimental Mesial Temporal Lobe Epilepsy. Mol Neurobiol 2024; 61:2367-2389. [PMID: 37874479 PMCID: PMC10973041 DOI: 10.1007/s12035-023-03692-2] [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: 07/11/2023] [Accepted: 10/04/2023] [Indexed: 10/25/2023]
Abstract
Structural epilepsies display complex immune activation signatures. However, it is unclear which neuroinflammatory pathways drive pathobiology. Transcriptome studies of brain resections from mesial temporal lobe epilepsy (mTLE) patients revealed a dysregulation of transforming growth factor β, interferon α/β, and nuclear factor erythroid 2-related factor 2 pathways. Since these pathways are regulated by ubiquitin-specific proteases (USP), in particular USP15, we hypothesized that USP15 blockade may provide therapeutic relief in treatment-resistant epilepsies. For validation, transgenic mice which either constitutively or inducibly lack Usp15 gene expression underwent intrahippocampal kainate injections to induce mTLE. We show that the severity of status epilepticus is unaltered in mice constitutively lacking Usp15 compared to wild types. Cell death, reactive gliosis, and changes in the inflammatory transcriptome were pronounced at 4 days after kainate injection. However, these brain inflammation signatures did not differ between genotypes. Likewise, induced deletion of Usp15 in chronic epilepsy did not affect seizure generation, cell death, gliosis, or the transcriptome. Concordantly, siRNA-mediated knockdown of Usp15 in a microglial cell line did not impact inflammatory responses in the form of cytokine release. Our data show that a lack of USP15 is insufficient to modulate the expression of relevant neuroinflammatory pathways in an mTLE mouse model and do not support targeting USP15 as a therapeutic approach for pharmacoresistant epilepsy.
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Affiliation(s)
- Ute Häussler
- Experimental Epilepsy Research, Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Breisacher Strasse 64, 79106, Freiburg, Germany.
- BrainLinks-BrainTools Center, University of Freiburg, Georges-Koehler-Allee 201, 79110, Freiburg, Germany.
| | - João Neres
- Early Solutions, UCB Biopharma SRL, Chemin du Foriest, 1420, Braine L'Alleud, Belgium
| | - Catherine Vandenplas
- Early Solutions, UCB Biopharma SRL, Chemin du Foriest, 1420, Braine L'Alleud, Belgium
| | - Caroline Eykens
- Early Solutions, UCB Biopharma SRL, Chemin du Foriest, 1420, Braine L'Alleud, Belgium
| | - Irena Kadiu
- Early Solutions, UCB Biopharma SRL, Chemin du Foriest, 1420, Braine L'Alleud, Belgium
| | - Carolin Schramm
- Early Solutions, UCB Biopharma SRL, Chemin du Foriest, 1420, Braine L'Alleud, Belgium
| | - Renaud Fleurance
- Early Solutions, UCB Biopharma SRL, Chemin du Foriest, 1420, Braine L'Alleud, Belgium
| | - Phil Stanley
- Early Development Statistics, UCB Celltech, 208 Bath Road, Slough, Berkshire, SL1 3WE, UK
| | - Patrice Godard
- Early Solutions, UCB Biopharma SRL, Chemin du Foriest, 1420, Braine L'Alleud, Belgium
| | - Laurane de Mot
- Early Solutions, UCB Biopharma SRL, Chemin du Foriest, 1420, Braine L'Alleud, Belgium
| | - Jonathan van Eyll
- Early Solutions, UCB Biopharma SRL, Chemin du Foriest, 1420, Braine L'Alleud, Belgium
| | - Klaus-Peter Knobeloch
- Institute for Neuropathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Breisacher Strasse 64, 79106, Freiburg, Germany.
- CIBSS - Centre for Integrative Biological Signalling Studies, Freiburg, Germany.
| | - Carola A Haas
- Experimental Epilepsy Research, Department of Neurosurgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Breisacher Strasse 64, 79106, Freiburg, Germany
- BrainLinks-BrainTools Center, University of Freiburg, Georges-Koehler-Allee 201, 79110, Freiburg, Germany
- Center for Basics in NeuroModulation, Faculty of Medicine, University of Freiburg, 79106, Freiburg, Germany
- Bernstein Center Freiburg, University of Freiburg, Hansastr. 9a, 79104, Freiburg, Germany
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Bolhuis DL, Emanuele MJ, Brown NG. Friend or foe? Reciprocal regulation between E3 ubiquitin ligases and deubiquitinases. Biochem Soc Trans 2024; 52:241-267. [PMID: 38414432 PMCID: PMC11349938 DOI: 10.1042/bst20230454] [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: 12/19/2023] [Revised: 01/31/2024] [Accepted: 02/06/2024] [Indexed: 02/29/2024]
Abstract
Protein ubiquitination is a post-translational modification that entails the covalent attachment of the small protein ubiquitin (Ub), which acts as a signal to direct protein stability, localization, or interactions. The Ub code is written by a family of enzymes called E3 Ub ligases (∼600 members in humans), which can catalyze the transfer of either a single ubiquitin or the formation of a diverse array of polyubiquitin chains. This code can be edited or erased by a different set of enzymes termed deubiquitinases (DUBs; ∼100 members in humans). While enzymes from these distinct families have seemingly opposing activities, certain E3-DUB pairings can also synergize to regulate vital cellular processes like gene expression, autophagy, innate immunity, and cell proliferation. In this review, we highlight recent studies describing Ub ligase-DUB interactions and focus on their relationships.
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Affiliation(s)
- Derek L Bolhuis
- Department of Biochemistry and Biophysics, UNC Chapel Hill School of Medicine, Chapel Hill, NC, 27599
| | - Michael J Emanuele
- Department of Pharmacology and Lineberger Comprehensive Care Center, UNC Chapel Hill School of Medicine, Chapel Hill, NC, 27599
| | - Nicholas G Brown
- Department of Pharmacology and Lineberger Comprehensive Care Center, UNC Chapel Hill School of Medicine, Chapel Hill, NC, 27599
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Ma X, Ma J, Leng T, Yuan Z, Hu T, Liu Q, Shen T. Advances in oxidative stress in pathogenesis of diabetic kidney disease and efficacy of TCM intervention. Ren Fail 2023; 45:2146512. [PMID: 36762989 PMCID: PMC9930779 DOI: 10.1080/0886022x.2022.2146512] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/11/2023] Open
Abstract
Diabetic kidney disease (DKD) is a common complication of diabetes and has become the leading cause of end-stage kidney disease. The pathogenesis of DKD is complicated, and oxidative stress is considered as a core of DKD onset. High glucose can lead to increased production of reactive oxygen species (ROS) via the polyol, PKC, AGE/RAGE and hexosamine pathways, resulting in enhanced oxidative stress response. In this way, pathways such as PI3K/Akt, TGF-β1/p38-MAPK and NF-κB are activated, inducing endothelial cell apoptosis, inflammation, autophagy and fibrosis that cause histologic and functional abnormalities of the kidney and finally result in kidney injury. Presently, the treatment for DKD remains an unresolved issue. Traditional Chinese medicine (TCM) has unique advantages for DKD prevention and treatment attributed to its multi-target, multi-component, and multi-pathway characteristics. Numerous studies have proved that Chinese herbs (e.g., Golden Thread, Kudzuvine Root, Tripterygium glycosides, and Ginseng) and patent medicines (e.g., Shenshuaining Tablet, Compound Rhizoma Coptidis Capsule, and Zishen Tongluo Granule) are effective for DKD treatment. The present review described the role of oxidative stress in DKD pathogenesis and the effect of TCM intervention for DKD prevention and treatment, in an attempt to provide evidence for clinical practice.
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Affiliation(s)
- Xiaoju Ma
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China,School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jingru Ma
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tian Leng
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Zhongzhu Yuan
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tingting Hu
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qiuyan Liu
- School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Tao Shen
- School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, China,CONTACT Tao Shen School of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu611137, China
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Abstract
Ubiquitination is an essential regulator of most, if not all, signalling pathways, and defects in cellular signalling are central to cancer initiation, progression and, eventually, metastasis. The attachment of ubiquitin signals by E3 ubiquitin ligases is directly opposed by the action of approximately 100 deubiquitinating enzymes (DUBs) in humans. Together, DUBs and E3 ligases coordinate ubiquitin signalling by providing selectivity for different substrates and/or ubiquitin signals. The balance between ubiquitination and deubiquitination is exquisitely controlled to ensure properly coordinated proteostasis and response to cellular stimuli and stressors. Not surprisingly, then, DUBs have been associated with all hallmarks of cancer. These relationships are often complex and multifaceted, highlighted by the implication of multiple DUBs in certain hallmarks and by the impact of individual DUBs on multiple cancer-associated pathways, sometimes with contrasting cancer-promoting and cancer-inhibiting activities, depending on context and tumour type. Although it is still understudied, the ever-growing knowledge of DUB function in cancer physiology will eventually identify DUBs that warrant specific inhibition or activation, both of which are now feasible. An integrated appreciation of the physiological consequences of DUB modulation in relevant cancer models will eventually lead to the identification of patient populations that will most likely benefit from DUB-targeted therapies.
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Affiliation(s)
- Grant Dewson
- Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
- Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
| | - Pieter J A Eichhorn
- Curtin Medical School, Curtin University, Perth, Western Australia, Australia.
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
| | - David Komander
- Ubiquitin Signalling Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.
- Department of Medical Biology, University of Melbourne, Melbourne, Victoria, Australia.
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Rastogi S, Mishra SS, Arora MK, Kaithwas G, Banerjee S, Ravichandiran V, Roy S, Singh L. Lactate acidosis and simultaneous recruitment of TGF-β leads to alter plasticity of hypoxic cancer cells in tumor microenvironment. Pharmacol Ther 2023; 250:108519. [PMID: 37625521 DOI: 10.1016/j.pharmthera.2023.108519] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 08/08/2023] [Accepted: 08/21/2023] [Indexed: 08/27/2023]
Abstract
Lactate acidosis is often observed in the tumor microenvironment (TME) of solid tumors. This is because glucose breaks down quickly via glycolysis, causing lactate acidity. Lactate is harmful to healthy cells, but is a major oncometabolite for solid cancer cells that do not receive sufficient oxygen. As an oncometabolite, it helps tumor cells perform different functions, which helps solid hypoxic tumor cells spread to other parts of the body. Studies have shown that the acidic TME contains VEGF, Matrix metalloproteinases (MMPs), cathepsins, and transforming growth factor-β (TGF-β), all of which help spread in direct and indirect ways. Although each cytokine is important in its own manner in the TME, TGF-β has received much attention for its role in metastatic transformation. Several studies have shown that lactate acidosis can cause TGF-β expression in solid hypoxic cancers. TGF-β has also been reported to increase the production of fatty acids, making cells more resistant to treatment. TGF-β has also been shown to control the expression of VEGF and MMPs, which helps solid hypoxic tumors become more aggressive by helping them spread and create new blood vessels through an unknown process. The role of TGF-β under physiological conditions has been described previously. In this study, we examined the role of TGF-β, which is induced by lactate acidosis, in the spread of solid hypoxic cancer cells. We also found that TGF-β and lactate work together to boost fatty acid production, which helps angiogenesis and invasiveness.
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Affiliation(s)
- Saumya Rastogi
- School of Pharmaceutical & Population Health Informatics, DIT University, Dehardun, Uttarakhand-248009, India
| | - Shashank Shekher Mishra
- School of Pharmaceutical & Population Health Informatics, DIT University, Dehardun, Uttarakhand-248009, India
| | - Mandeep Kumar Arora
- School of Pharmaceutical & Population Health Informatics, DIT University, Dehardun, Uttarakhand-248009, India
| | - Gaurav Kaithwas
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University (A central university), Lucknow, Uttar Pradesh, India
| | - Sugato Banerjee
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Kolkata, West Bengal 700054, India
| | - Velayutham Ravichandiran
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Kolkata, West Bengal 700054, India
| | - Subhadeep Roy
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research, Kolkata, West Bengal 700054, India.
| | - Lakhveer Singh
- School of Pharmaceutical & Population Health Informatics, DIT University, Dehardun, Uttarakhand-248009, India.
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Opposing USP19 splice variants in TGF-β signaling and TGF-β-induced epithelial-mesenchymal transition of breast cancer cells. Cell Mol Life Sci 2023; 80:43. [PMID: 36646950 PMCID: PMC9842591 DOI: 10.1007/s00018-022-04672-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Revised: 11/29/2022] [Accepted: 12/13/2022] [Indexed: 01/18/2023]
Abstract
Ubiquitin-specific protease (USP)19 is a deubiquitinating enzyme that regulates the stability and function of multiple proteins, thereby controlling various biological responses. The alternative splicing of USP19 results in the expression of two major encoded variants that are localized to the endoplasmic reticulum (ER) (USP19-ER) and cytoplasm (USP19-CY). The importance of alternative splicing for the function of USP19 remains unclear. Here, we demonstrated that USP19-CY promotes TGF-β signaling by directly interacting with TGF-β type I receptor (TβRI) and protecting it from degradation at the plasma membrane. In contrast, USP19-ER binds to and sequesters TβRI in the ER. By decreasing cell surface TβRI levels, USP19-ER inhibits TGF-β/SMAD signaling in a deubiquitination-independent manner. Moreover, USP19-ER inhibits TGF-β-induced epithelial-mesenchymal transition (EMT), whereas USP19-CY enhances EMT, as well as the migration and extravasation of breast cancer cells. Furthermore, USP19-CY expression is correlated with poor prognosis and is higher in breast cancer tissues than in adjacent normal tissues. Notably, the splicing modulator herboxidiene inhibits USP19-CY, increases USP19-ER expression and suppresses breast cancer cell migration. Targeting USP19 splicing or its deubiquitinating activity may have potential therapeutic effects on breast cancer.
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Mitoxantrone stacking does not define the active or inactive state of USP15 catalytic domain. J Struct Biol 2022; 214:107862. [DOI: 10.1016/j.jsb.2022.107862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 04/25/2022] [Accepted: 05/14/2022] [Indexed: 11/23/2022]
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Li YC, Cai SW, Shu YB, Chen MW, Shi Z. USP15 in Cancer and Other Diseases: From Diverse Functionsto Therapeutic Targets. Biomedicines 2022; 10:474. [PMID: 35203682 PMCID: PMC8962386 DOI: 10.3390/biomedicines10020474] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 02/09/2022] [Accepted: 02/13/2022] [Indexed: 12/10/2022] Open
Abstract
The process of protein ubiquitination and deubiquitination plays an important role in maintaining protein stability and regulating signal pathways, and protein homeostasis perturbations may induce a variety of diseases. The deubiquitination process removes ubiquitin molecules from the protein, which requires the participation of deubiquitinating enzymes (DUBs). Ubiquitin-specific protease 15 (USP15) is a DUB that participates in many biological cell processes and regulates tumorigenesis. A dislocation catalytic triplet was observed in the USP15 structure, a conformation not observed in other USPs, except USP7, which makes USP15 appear to be unique. USP15 has been reported to be involved in the regulation of various cancers and diseases, and the reported substrate functions of USP15 are conflicting, suggesting that USP15 may act as both an oncogene and a tumor suppressor in different contexts. The importance and complexity of USP15 in the pathological processes remains unclear. Therefore, we reviewed the diverse biological functions of USP15 in cancers and other diseases, suggesting the potential of USP15 as an attractive therapeutic target.
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Affiliation(s)
- Yan-Chi Li
- Department of Cell Biology & Institute of Biomedicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China; (Y.-C.L.); (Y.-B.S.)
| | - Song-Wang Cai
- Department of Thoracic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou 510632, China;
| | - Yu-Bin Shu
- Department of Cell Biology & Institute of Biomedicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China; (Y.-C.L.); (Y.-B.S.)
| | - Mei-Wan Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 519000, China;
| | - Zhi Shi
- Department of Cell Biology & Institute of Biomedicine, MOE Key Laboratory of Tumor Molecular Biology, Guangdong Provincial Key Laboratory of Bioengineering Medicine, National Engineering Research Center of Genetic Medicine, College of Life Science and Technology, Jinan University, Guangzhou 510632, China; (Y.-C.L.); (Y.-B.S.)
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Hiraiwa M, Fukasawa K, Iezaki T, Sabit H, Horie T, Tokumura K, Iwahashi S, Murata M, Kobayashi M, Suzuki A, Park G, Kaneda K, Todo T, Hirao A, Nakada M, Hinoi E. SMURF2 phosphorylation at Thr249 modifies glioma stemness and tumorigenicity by regulating TGF-β receptor stability. Commun Biol 2022; 5:22. [PMID: 35017630 PMCID: PMC8752672 DOI: 10.1038/s42003-021-02950-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 12/03/2021] [Indexed: 01/17/2023] Open
Abstract
Glioma stem cells (GSCs) contribute to the pathogenesis of glioblastoma, the most malignant form of glioma. The implication and underlying mechanisms of SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) on the GSC phenotypes remain unknown. We previously demonstrated that SMURF2 phosphorylation at Thr249 (SMURF2Thr249) activates its E3 ubiquitin ligase activity. Here, we demonstrate that SMURF2Thr249 phosphorylation plays an essential role in maintaining GSC stemness and tumorigenicity. SMURF2 silencing augmented the self-renewal potential and tumorigenicity of patient-derived GSCs. The SMURF2Thr249 phosphorylation level was low in human glioblastoma pathology specimens. Introduction of the SMURF2T249A mutant resulted in increased stemness and tumorigenicity of GSCs, recapitulating the SMURF2 silencing. Moreover, the inactivation of SMURF2Thr249 phosphorylation increases TGF-β receptor (TGFBR) protein stability. Indeed, TGFBR1 knockdown markedly counteracted the GSC phenotypes by SMURF2T249A mutant. These findings highlight the importance of SMURF2Thr249 phosphorylation in maintaining GSC phenotypes, thereby demonstrating a potential target for GSC-directed therapy. Hiraiwa et al. show that phosphorylation of SMAD specific E3 ubiquitin protein ligase 2 (SMURF2) at Thr249 mediates ubiquitylation and degradation of the TGF-β receptor TGBR1 leading to loss of glioblastoma stem cell tumorigenic capacity. Their data elucidates a mechanism of regulation of the TGF-β signaling pathway that controls the stem cell status in glioblastoma.
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Affiliation(s)
- Manami Hiraiwa
- Department of Bioactive Molecules, Pharmacology, Gifu Pharmaceutical University, Gifu, 501-1196, Japan
| | - Kazuya Fukasawa
- Department of Bioactive Molecules, Pharmacology, Gifu Pharmaceutical University, Gifu, 501-1196, Japan
| | - Takashi Iezaki
- Department of Bioactive Molecules, Pharmacology, Gifu Pharmaceutical University, Gifu, 501-1196, Japan.
| | - Hemragul Sabit
- Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Tetsuhiro Horie
- Department of Bioactive Molecules, Pharmacology, Gifu Pharmaceutical University, Gifu, 501-1196, Japan
| | - Kazuya Tokumura
- Department of Bioactive Molecules, Pharmacology, Gifu Pharmaceutical University, Gifu, 501-1196, Japan
| | - Sayuki Iwahashi
- Department of Bioactive Molecules, Pharmacology, Gifu Pharmaceutical University, Gifu, 501-1196, Japan
| | - Misato Murata
- Department of Bioactive Molecules, Pharmacology, Gifu Pharmaceutical University, Gifu, 501-1196, Japan
| | - Masaki Kobayashi
- Department of Bioactive Molecules, Pharmacology, Gifu Pharmaceutical University, Gifu, 501-1196, Japan
| | - Akane Suzuki
- Department of Bioactive Molecules, Pharmacology, Gifu Pharmaceutical University, Gifu, 501-1196, Japan
| | - Gyujin Park
- Department of Bioactive Molecules, Pharmacology, Gifu Pharmaceutical University, Gifu, 501-1196, Japan
| | - Katsuyuki Kaneda
- Laboratory of Molecular Pharmacology, Division of Pharmaceutical Sciences, Kanazawa University Graduate School, Kanazawa, Ishikawa, 920-1192, Japan
| | - Tomoki Todo
- Division of Innovative Cancer Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Atsushi Hirao
- Cancer and Stem Cell Research Program, Division of Molecular Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa, Japan.,WPI Nano Life Science Institute (WPI-Nano LSI), Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Mitsutoshi Nakada
- Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa, Japan
| | - Eiichi Hinoi
- Department of Bioactive Molecules, Pharmacology, Gifu Pharmaceutical University, Gifu, 501-1196, Japan. .,United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan.
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USP15 antagonizes CRL4 CRBN-mediated ubiquitylation of glutamine synthetase and neosubstrates. Proc Natl Acad Sci U S A 2021; 118:2111391118. [PMID: 34583995 DOI: 10.1073/pnas.2111391118] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/30/2021] [Indexed: 12/13/2022] Open
Abstract
Targeted protein degradation by the ubiquitin-proteasome system represents a new strategy to destroy pathogenic proteins in human diseases, including cancer and neurodegenerative diseases. The immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide have revolutionized the treatment of patients with multiple myeloma (MM) and other hematologic malignancies, but almost all patients eventually develop resistance to IMiDs. CRBN, a substrate receptor of CUL4-RBX1-DDB1-CRBN (CRL4CRBN) E3 ubiquitin ligase, is a direct target for thalidomide teratogenicity and antitumor activity of IMiDs (now known as Cereblon E3 ligase modulators: CELMoDs). Despite recent advances in developing potent CELMoDs and CRBN-based proteolysis-targeting chimeras (PROTACs), many questions apart from clinical efficacy remain unanswered. CRBN is required for the action of IMiDs, but its protein expression levels do not correlate with intrinsic resistance to IMiDs in MM cells, suggesting other factors involved in regulating resistance to IMiDs. Our recent work revealed that the CRL4CRBN-p97 pathway is required for degradation of natural substrate glutamine synthetase (GS) and neosubstrates. Here, I show that USP15 is a key regulator of the CRL4CRBN-p97 pathway to control stability of GS and neosubstrates IKZF1, IKZF3, CK1-α, RNF166, GSPT1, and BRD4, all of which are crucial drug targets in different types of cancer. USP15 antagonizes ubiquitylation of CRL4CRBN target proteins, thereby preventing their degradation. Notably, USP15 is highly expressed in IMiD-resistant cells, and depletion of USP15 sensitizes these cells to lenalidomide. Inhibition of USP15 represents a valuable therapeutic opportunity to potentiate CELMoD and CRBN-based PROTAC therapies for the treatment of cancer.
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13
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Wang XL, Feng ST, Wang ZZ, Yuan YH, Chen NH, Zhang Y. Parkin, an E3 Ubiquitin Ligase, Plays an Essential Role in Mitochondrial Quality Control in Parkinson's Disease. Cell Mol Neurobiol 2021; 41:1395-1411. [PMID: 32623547 PMCID: PMC11448647 DOI: 10.1007/s10571-020-00914-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 06/27/2020] [Indexed: 02/06/2023]
Abstract
Parkinson's disease (PD), as one of the complex neurodegenerative disorders, affects millions of aged people. Although the precise pathogenesis remains mostly unknown, a significant number of studies have demonstrated that mitochondrial dysfunction acts as a major role in the pathogeny of PD. Both nuclear and mitochondrial DNA mutations can damage mitochondrial integrity. Especially, mutations in several genes that PD-linked have a closed association with mitochondrial dysfunction (e.g., Parkin, PINK1, DJ-1, alpha-synuclein, and LRRK2). Parkin, whose mutation causes autosomal-recessive juvenile parkinsonism, plays an essential role in mitochondrial quality control of mitochondrial biogenesis, mitochondrial dynamics, and mitophagy. Therefore, we summarized the advanced studies of Parkin's role in mitochondrial quality control and hoped it could be studied further as a therapeutic target for PD.
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Affiliation(s)
- Xiao-Le Wang
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Si-Tong Feng
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Zhen-Zhen Wang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yu-He Yuan
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Nai-Hong Chen
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica & Neuroscience Center, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Yi Zhang
- Department of Anatomy, School of Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China.
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14
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Zhong M, Zhou L, Fang Z, Yao YY, Zou JP, Xiong JP, Xiang XJ, Deng J. Ubiquitin-specific protease 15 contributes to gastric cancer progression by regulating the Wnt/β-catenin signaling pathway. World J Gastroenterol 2021; 27:4221-4235. [PMID: 34326621 PMCID: PMC8311539 DOI: 10.3748/wjg.v27.i26.4221] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/27/2021] [Accepted: 06/16/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Ubiquitin-specific protease 15 (USP15) is an important member of the ubiquitin-specific protease family, the largest deubiquitinase subfamily, whose expression is dysregulated in many types of cancer. However, the biological function and the underlying mechanisms of USP15 in gastric cancer (GC) progression have not been elucidated.
AIM To explore the biological role and underlying mechanisms of USP15 in GC progression.
METHODS Bioinformatics databases and western blot analysis were utilized to determine the expression of USP15 in GC. Immunohistochemistry was performed to evaluate the correlation between USP15 expression and clinicopathological characteristics of patients with GC. A loss- and gain-of-function experiment was used to investigate the biological effects of USP15 on GC carcinogenesis. RNA sequencing, immunofluorescence, and western blotting were performed to explore the potential mechanism by which USP15 exerts its oncogenic functions.
RESULTS USP15 was up-regulated in GC tissue and cell lines. The expression level of USP15 was positively correlated with clinical characteristics (tumor size, depth of invasion, lymph node involvement, tumor-node-metastasis stage, perineural invasion, and vascular invasion), and was related to poor prognosis. USP15 knockdown significantly inhibited cell proliferation, invasion and epithelial-mesenchymal transition (EMT) of GC in vitro, while overexpression of USP15 promoted these processes. Knockdown of USP15 inhibited tumor growth in vivo. Mechanistically, RNA sequencing analysis showed that USP15 regulated the Wnt signaling pathway in GC. Western blotting confirmed that USP15 silencing led to significant down-regulation of β-catenin and Wnt/β-catenin downstream genes (c-myc and cyclin D1), while overexpression of USP15 yielded an opposite result and USP15 mutation had no change. Immunofluorescence indicated that USP15 promoted nuclear translocation of β-catenin, suggesting activation of the Wnt/β-catenin signaling pathway, which may be the critical mechanism promoting GC progression. Finally, rescue experiments showed that the effect of USP15 on gastric cancer progression was dependent on Wnt/β-catenin pathway.
CONCLUSION USP15 promotes cell proliferation, invasion and EMT progression of GC via regulating the Wnt/β-catenin pathway, which suggests that USP15 is a novel potential therapeutic target for GC.
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Affiliation(s)
- Min Zhong
- Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Ling Zhou
- Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Zhi Fang
- Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Yang-Yang Yao
- Department of Cancer Center, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jian-Ping Zou
- Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jian-Ping Xiong
- Department of Cancer Center, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Xiao-Jun Xiang
- Department of Cancer Center, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
| | - Jun Deng
- Department of Jiangxi Key Laboratory for Individualized Cancer Therapy, The First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
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15
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Cao Y, Yang Z, Chen Y, Jiang S, Wu Z, Ding B, Yang Y, Jin Z, Tang H. An Overview of the Posttranslational Modifications and Related Molecular Mechanisms in Diabetic Nephropathy. Front Cell Dev Biol 2021; 9:630401. [PMID: 34124032 PMCID: PMC8193943 DOI: 10.3389/fcell.2021.630401] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 04/12/2021] [Indexed: 01/14/2023] Open
Abstract
Diabetic nephropathy (DN), a common diabetic microvascular complication, is characterized by its complex pathogenesis, higher risk of mortality, and the lack of effective diagnosis and treatment methods. Many studies focus on the diagnosis and treatment of diabetes mellitus (DM) and have reported that the pathophysiology of DN is very complex, involving many molecules and abnormal cellular activities. Given the respective pivotal roles of NF-κB, Nrf2, and TGF-β in inflammation, oxidative stress, and fibrosis during DN, we first review the effect of posttranslational modifications on these vital molecules in DN. Then, we describe the relationship between these molecules and related abnormal cellular activities in DN. Finally, we discuss some potential directions for DN treatment and diagnosis. The information reviewed here may be significant in the design of further studies to identify valuable therapeutic targets for DN.
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Affiliation(s)
- Yu Cao
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, The Air Force Medical University, Xi'an, China
| | - Zhao Yang
- Department of Gynaecology and Obstetrics, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ying Chen
- Department of Hematology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Shuai Jiang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Zhen Wu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Baoping Ding
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Yang Yang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences, Northwest University, Xi'an, China
| | - Zhenxiao Jin
- Department of Cardiovascular Surgery, Xijing Hospital, The Air Force Medical University, Xi'an, China
| | - Haifeng Tang
- Department of Chinese Materia Medica and Natural Medicines, School of Pharmacy, The Air Force Medical University, Xi'an, China
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16
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USP15: a review of its implication in immune and inflammatory processes and tumor progression. Genes Immun 2021; 22:12-23. [PMID: 33824497 DOI: 10.1038/s41435-021-00125-9] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/09/2021] [Accepted: 03/17/2021] [Indexed: 02/01/2023]
Abstract
The covalent post-translational modification of proteins by ubiquitination not only influences protein stability and half-life, but also several aspects of protein function including enzymatic activity, sub-cellular localization, and interactions with binding partners. Protein ubiquitination status is determined by the action of large families of ubiquitin ligases and deubiquitinases, whose combined activities regulate many physiological and cellular pathways. The Ubiquitin Specific Protease (USP) family is one of 8 subfamilies of deubiquitinating enzymes composed of more than 50 members. Recent studies have shown that USP15 plays a critical role in regulating many aspects of immune and inflammatory function of leukocytes in response to a broad range of infectious and autoimmune insults and following tissue damage. USP15 regulated pathways reviewed herein include TLR signaling, RIG-I signaling, NF-kB, and IRF3/IRF7-dependent transcription for production of pro-inflammatory cytokines and type I interferons. In addition, USP15 has been found to regulate pathways implicated in tumor onset and progression such as p53, and TGF-β signaling, but also influences the leukocytes-determined immune and inflammatory microenvironment of tumors to affect progression and outcome. Hereby reviewed are recent studies of USP15 in model cell lines in vitro, and in mutant mice in vivo with reference to available human clinical datasets.
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17
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The Multifaceted Roles of USP15 in Signal Transduction. Int J Mol Sci 2021; 22:ijms22094728. [PMID: 33946990 PMCID: PMC8125482 DOI: 10.3390/ijms22094728] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/26/2021] [Accepted: 04/26/2021] [Indexed: 02/07/2023] Open
Abstract
Ubiquitination and deubiquitination are protein post-translational modification processes that have been recognized as crucial mediators of many complex cellular networks, including maintaining ubiquitin homeostasis, controlling protein stability, and regulating several signaling pathways. Therefore, some of the enzymes involved in ubiquitination and deubiquitination, particularly E3 ligases and deubiquitinases, have attracted attention for drug discovery. Here, we review recent findings on USP15, one of the deubiquitinases, which regulates diverse signaling pathways by deubiquitinating vital target proteins. Even though several basic previous studies have uncovered the versatile roles of USP15 in different signaling networks, those have not yet been systematically and specifically reviewed, which can provide important information about possible disease markers and clinical applications. This review will provide a comprehensive overview of our current understanding of the regulatory mechanisms of USP15 on different signaling pathways for which dynamic reverse ubiquitination is a key regulator.
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18
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Advances in the Development Ubiquitin-Specific Peptidase (USP) Inhibitors. Int J Mol Sci 2021; 22:ijms22094546. [PMID: 33925279 PMCID: PMC8123678 DOI: 10.3390/ijms22094546] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/03/2021] [Accepted: 04/07/2021] [Indexed: 02/06/2023] Open
Abstract
Ubiquitylation and deubiquitylation are reversible protein post-translational modification (PTM) processes involving the regulation of protein degradation under physiological conditions. Loss of balance in this regulatory system can lead to a wide range of diseases, such as cancer and inflammation. As the main members of the deubiquitinases (DUBs) family, ubiquitin-specific peptidases (USPs) are closely related to biological processes through a variety of molecular signaling pathways, including DNA damage repair, p53 and transforming growth factor-β (TGF-β) pathways. Over the past decade, increasing attention has been drawn to USPs as potential targets for the development of therapeutics across diverse therapeutic areas. In this review, we summarize the crucial roles of USPs in different signaling pathways and focus on advances in the development of USP inhibitors, as well as the methods of screening and identifying USP inhibitors.
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19
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Rossio V, Paulo JA, Chick J, Brasher B, Gygi SP, King RW. Proteomics of broad deubiquitylase inhibition unmasks redundant enzyme function to reveal substrates and assess enzyme specificity. Cell Chem Biol 2021; 28:487-502.e5. [PMID: 33417828 PMCID: PMC8052291 DOI: 10.1016/j.chembiol.2020.12.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 10/30/2020] [Accepted: 12/16/2020] [Indexed: 01/30/2023]
Abstract
Deubiquitylating enzymes (DUBs) counteract ubiquitylation to control stability or activity of substrates. Identification of DUB substrates is challenging because multiple DUBs can act on the same substrate, thwarting genetic approaches. Here, we circumvent redundancy by chemically inhibiting multiple DUBs simultaneously in Xenopus egg extract. We used quantitative mass spectrometry to identify proteins whose ubiquitylation or stability is altered by broad DUB inhibition, and confirmed their DUB-dependent regulation with human orthologs, demonstrating evolutionary conservation. We next extended this method to profile DUB specificity. By adding recombinant DUBs to extract where DUB activity was broadly inhibited, but ubiquitylation and degradation were active at physiological rates, we profiled the ability of DUBs to rescue degradation of these substrates. We found that USP7 has a unique ability to broadly antagonize degradation. Together, we present an approach to identify DUB substrates and characterize DUB specificity that overcomes challenges posed by DUB redundancy.
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Affiliation(s)
- Valentina Rossio
- Department of Cell Biology, Blavatnik Institute at Harvard Medical School, Boston, MA 02115, USA
| | - Joao A Paulo
- Department of Cell Biology, Blavatnik Institute at Harvard Medical School, Boston, MA 02115, USA
| | - Joel Chick
- Department of Cell Biology, Blavatnik Institute at Harvard Medical School, Boston, MA 02115, USA
| | - Bradley Brasher
- Boston Biochem, a Bio-Techne Brand, Cambridge, MA 02139, USA
| | - Steven P Gygi
- Department of Cell Biology, Blavatnik Institute at Harvard Medical School, Boston, MA 02115, USA
| | - Randall W King
- Department of Cell Biology, Blavatnik Institute at Harvard Medical School, Boston, MA 02115, USA.
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20
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Yang L, Zhou W, Lin H. Posttranslational Modifications of Smurfs: Emerging Regulation in Cancer. Front Oncol 2021; 10:610663. [PMID: 33718111 PMCID: PMC7950759 DOI: 10.3389/fonc.2020.610663] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 12/30/2020] [Indexed: 12/14/2022] Open
Abstract
Smad ubiquitination regulatory factors (Smurfs) belong to the Nedd4 subfamily of HECT-type E3 ubiquitin ligases. Under normal situations, Smurfs are exactly managed by upstream regulators, and thereby strictly control tumor biological processes, including cell growth, differentiation, apoptosis, polarization, epithelial mesenchymal transition (EMT), and invasion. Disruption of Smurf activity has been implicated in cancer progression, and Smurf activity is controlled by a series of posttranslational modifications (PTMs), including phosphorylation, ubiquitination, neddylation, sumoylation, and methylation. The effect and function of Smurfs depend on PTMs and regulate biological processes. Specifically, these modifications regulate the functional expression of Smurfs by affecting protein degradation and protein interactions. In this review, we summarize the complexity and diversity of Smurf PTMs from biochemical and biological perspectives and highlight the understanding of their roles in cancer.
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Affiliation(s)
- Longtao Yang
- Second Clinical Medical School, Nanchang University, Nanchang, China
| | - Wenwen Zhou
- Second Clinical Medical School, Nanchang University, Nanchang, China
| | - Hui Lin
- Department of Pathophysiology, School of Basic Medical Sciences, Nanchang University, Nanchang, China
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21
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Jiang B, Zhou L, Lu J, Wang Y, Liu C, Liang Z, Zhou W, You L, Guo J. Clinicopathological and prognostic significance of ubiquitin-specific peptidase 15 and its relationship with transforming growth factor-β receptors in patients with pancreatic ductal adenocarcinoma. J Gastroenterol Hepatol 2021; 36:507-515. [PMID: 32875609 DOI: 10.1111/jgh.15244] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 08/10/2020] [Accepted: 08/26/2020] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND AIM Ubiquitin-specific peptidase 15 (USP15) has been correlated to aggressive oncogenic behavior in several types of carcinomas, but its function in pancreatic ductal adenocarcinoma (PDAC) has not been clarified. This study aimed to evaluate the clinicopathological and prognostic value of USP15 and its relationship with transforming growth factor-β (TGF-β) receptors (TβRs) in PDAC. METHODS By immunohistochemical staining of tissue microarrays, the expression patterns of USP15 and TβRs were retrospectively analyzed in 287 PDAC patients who underwent radical surgical resection without neoadjuvant therapy. Cancer-specific survival was compared based on USP15 expression, and the correlations between USP15 and TβRs were analyzed. RESULTS Ubiquitin-specific peptidase 15 expression in tumor tissues was significantly higher than that in para-tumor tissues (P < 0.0001), and high USP15 expression was associated with the pathological N (pN) stage (P = 0.033). In addition, high USP15 expression was significantly associated with shorter cancer-specific survival (P = 0.019). Univariate analyses showed that high USP15 expression (P = 0.024), a poor histopathological grade (P = 0.003), and the pN1 stage (P = 0.009) were significantly correlated with shorter survival. Although the independent prognostic value of USP15 alone was not established, the combination of USP15 and the histological grade was identified as an independent prognostic factor in multivariate analyses (P = 0.015). USP15 expression was correlated with TβR-I, TβR-II, or TβR-III expression in PDAC. CONCLUSIONS High USP15 expression is a potential prognostic indicator in patients with PDAC, and it might affect the TGF-β signaling pathway in PDAC.
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Affiliation(s)
- Bolun Jiang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Li Zhou
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Jun Lu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Yizhi Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Chengxi Liu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Zhiyong Liang
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Weixun Zhou
- Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
| | - Junchao Guo
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
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22
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Basar MA, Beck DB, Werner A. Deubiquitylases in developmental ubiquitin signaling and congenital diseases. Cell Death Differ 2021; 28:538-556. [PMID: 33335288 PMCID: PMC7862630 DOI: 10.1038/s41418-020-00697-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/20/2020] [Accepted: 11/24/2020] [Indexed: 02/06/2023] Open
Abstract
Metazoan development from a one-cell zygote to a fully formed organism requires complex cellular differentiation and communication pathways. To coordinate these processes, embryos frequently encode signaling information with the small protein modifier ubiquitin, which is typically attached to lysine residues within substrates. During ubiquitin signaling, a three-step enzymatic cascade modifies specific substrates with topologically unique ubiquitin modifications, which mediate changes in the substrate's stability, activity, localization, or interacting proteins. Ubiquitin signaling is critically regulated by deubiquitylases (DUBs), a class of ~100 human enzymes that oppose the conjugation of ubiquitin. DUBs control many essential cellular functions and various aspects of human physiology and development. Recent genetic studies have identified mutations in several DUBs that cause developmental disorders. Here we review principles controlling DUB activity and substrate recruitment that allow these enzymes to regulate ubiquitin signaling during development. We summarize key mechanisms of how DUBs control embryonic and postnatal differentiation processes, highlight developmental disorders that are caused by mutations in particular DUB members, and describe our current understanding of how these mutations disrupt development. Finally, we discuss how emerging tools from human disease genetics will enable the identification and study of novel congenital disease-causing DUBs.
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Affiliation(s)
- Mohammed A Basar
- Stem Cell Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA
| | - David B Beck
- Stem Cell Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA
- Metabolic, Cardiovascular and Inflammatory Disease Genomics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Achim Werner
- Stem Cell Biochemistry Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, 20892, USA.
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23
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Sinha A, Iyengar PV, ten Dijke P. E3 Ubiquitin Ligases: Key Regulators of TGFβ Signaling in Cancer Progression. Int J Mol Sci 2021; 22:E476. [PMID: 33418880 PMCID: PMC7825147 DOI: 10.3390/ijms22020476] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 12/25/2020] [Accepted: 12/29/2020] [Indexed: 02/07/2023] Open
Abstract
Transforming growth factor β (TGFβ) is a secreted growth and differentiation factor that influences vital cellular processes like proliferation, adhesion, motility, and apoptosis. Regulation of the TGFβ signaling pathway is of key importance to maintain tissue homeostasis. Perturbation of this signaling pathway has been implicated in a plethora of diseases, including cancer. The effect of TGFβ is dependent on cellular context, and TGFβ can perform both anti- and pro-oncogenic roles. TGFβ acts by binding to specific cell surface TGFβ type I and type II transmembrane receptors that are endowed with serine/threonine kinase activity. Upon ligand-induced receptor phosphorylation, SMAD proteins and other intracellular effectors become activated and mediate biological responses. The levels, localization, and function of TGFβ signaling mediators, regulators, and effectors are highly dynamic and regulated by a myriad of post-translational modifications. One such crucial modification is ubiquitination. The ubiquitin modification is also a mechanism by which crosstalk with other signaling pathways is achieved. Crucial effector components of the ubiquitination cascade include the very diverse family of E3 ubiquitin ligases. This review summarizes the diverse roles of E3 ligases that act on TGFβ receptor and intracellular signaling components. E3 ligases regulate TGFβ signaling both positively and negatively by regulating degradation of receptors and various signaling intermediates. We also highlight the function of E3 ligases in connection with TGFβ's dual role during tumorigenesis. We conclude with a perspective on the emerging possibility of defining E3 ligases as drug targets and how they may be used to selectively target TGFβ-induced pro-oncogenic responses.
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Affiliation(s)
| | | | - Peter ten Dijke
- Department of Cell and Chemical Biology and Oncode Institute, Leiden University Medical Center, 2300 RC Leiden, The Netherlands; (A.S.); (P.V.I.)
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24
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OTUD4 enhances TGFβ signalling through regulation of the TGFβ receptor complex. Sci Rep 2020; 10:15725. [PMID: 32973272 PMCID: PMC7519109 DOI: 10.1038/s41598-020-72791-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 09/02/2020] [Indexed: 11/18/2022] Open
Abstract
Systematic control of the transforming growth factor-β (TGFβ) pathway is essential to keep the amplitude and the intensity of downstream signalling at appropriate levels. Ubiquitination plays a crucial role in the general regulation of this pathway. Here we identify the deubiquitinating enzyme OTUD4 as a transcriptional target of the TGFβ pathway that functions through a positive feedback loop to enhance overall TGFβ activity. Interestingly we demonstrate that OTUD4 functions through both catalytically dependent and independent mechanisms to regulate TGFβ activity. Specifically, we find that OTUD4 enhances TGFβ signalling by promoting the membrane presence of TGFβ receptor I. Furthermore, we demonstrate that OTUD4 inactivates the TGFβ negative regulator SMURF2 suggesting that OTUD4 regulates multiple nodes of the TGFβ pathway to enhance TGFβ activity.
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25
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Bai Y, Ying Y. The Post-translational Modifications of Smurf2 in TGF-β Signaling. Front Mol Biosci 2020; 7:128. [PMID: 32733916 PMCID: PMC7358609 DOI: 10.3389/fmolb.2020.00128] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 06/02/2020] [Indexed: 12/18/2022] Open
Abstract
Smad ubiquitin regulatory factor 2 (Smurf2), an essential negative regulator of TGF-β signaling, ubiquitinates TGF-β receptors (TβRs) and Smad proteins, inducing their proteasomal degradation. Smurf2 plays crucial roles in regulating TGF-β signaling and maintaining normal cellular functions and tissue homeostasis; dysfunction of Smurf2 triggers abnormal TGF-β signaling in pathological states. Smurf2 has been reported as a potentially strong candidate for targeting therapies for related diseases. Recent work has begun to focus on the regulation of Smurf2 itself, and emerging evidence indicates that Smurf2 is regulated by post-translational modifications (PTMs) mechanisms. These mechanisms predominantly regulate the expression level and E3 ligase activity of Smurf2, strongly suggesting that this protein contributes to complicated roles under multiple pathophysiological conditions. In this review, we cover some significant and novel mechanisms of the PTMs that potentially control Smurf2 participation in TGF-β signaling, including ubiquitylation, SUMOylation, neddylation, phosphorylation, and methylation in order to provide a broad view of the depth and sophistication of Smurf2 function in TGF-β regulation, as well as perspectives for future therapeutic directions for its associated diseases.
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Affiliation(s)
- Yangjinming Bai
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang, China.,Nanchang Joint Program, Queen Mary School, Nanchang University, Nanchang, China
| | - Ying Ying
- Jiangxi Province Key Laboratory of Tumor Pathogens and Molecular Pathology and Department of Pathophysiology, Schools of Basic Medical Sciences, Nanchang University, Nanchang, China
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26
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Nielsen CP, MacGurn JA. Coupling Conjugation and Deconjugation Activities to Achieve Cellular Ubiquitin Dynamics. Trends Biochem Sci 2020; 45:427-439. [PMID: 32311336 DOI: 10.1016/j.tibs.2020.01.008] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 01/24/2020] [Accepted: 01/28/2020] [Indexed: 12/19/2022]
Abstract
In eukaryotic cells, proteome remodeling is mediated by the ubiquitin-proteasome system, which regulates protein degradation, trafficking, and signaling events in the cell. Interplay between the cellular proteome and ubiquitin is complex and dynamic and many regulatory features that support this system have only recently come into focus. An unexpected recurring feature in this system is the physical interaction between E3 ubiquitin ligases and deubiquitylases (DUBs). Recent studies have reported on the regulatory significance of DUB-E3 interactions and it is becoming clear that they play important but complicated roles in the regulation of diverse cellular processes. Here, we summarize the current understanding of interactions between ubiquitin conjugation and deconjugation machineries and we examine the regulatory logic of these enigmatic complexes.
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Affiliation(s)
- Casey P Nielsen
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA
| | - Jason A MacGurn
- Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN, USA.
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27
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Fu L, Cui CP, Zhang X, Zhang L. The functions and regulation of Smurfs in cancers. Semin Cancer Biol 2019; 67:102-116. [PMID: 31899247 DOI: 10.1016/j.semcancer.2019.12.023] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 11/10/2019] [Accepted: 12/26/2019] [Indexed: 02/06/2023]
Abstract
Smad ubiquitination regulatory factor 1 (Smurf1) and Smurf2 are HECT-type E3 ubiquitin ligases, and both Smurfs were initially identified to regulate Smad protein stability in the TGF-β/BMP signaling pathway. In recent years, Smurfs have exhibited E3 ligase-dependent and -independent activities in various kinds of cells. Smurfs act as either potent tumor promoters or tumor suppressors in different tumors by regulating biological processes, including metastasis, apoptosis, cell cycle, senescence and genomic stability. The regulation of Smurfs activity and expression has therefore emerged as a hot spot in tumor biology research. Further, the Smurf1- or Smurf2-deficient mice provide more in vivo clues for the functional study of Smurfs in tumorigenesis and development. In this review, we summarize these milestone findings and, in turn, reveal new avenues for the prevention and treatment of cancer by regulating Smurfs.
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Affiliation(s)
- Lin Fu
- Institute of Chronic Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao 266000, China
| | - Chun-Ping Cui
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China
| | - Xueli Zhang
- Department of General Surgery, Shanghai Fengxian Central Hospital Graduate Training Base, Fengxian Hospital, Southern Medical University, Shanghai, China.
| | - Lingqiang Zhang
- Institute of Chronic Disease, Qingdao Municipal Hospital, Qingdao University, Qingdao 266000, China; State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 100850, China; Peixian People's Hospital, Jiangsu Province 221600, China.
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28
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c-Met activation leads to the establishment of a TGFβ-receptor regulatory network in bladder cancer progression. Nat Commun 2019; 10:4349. [PMID: 31554791 PMCID: PMC6761206 DOI: 10.1038/s41467-019-12241-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 08/27/2019] [Indexed: 01/03/2023] Open
Abstract
Treatment of muscle-invasive bladder cancer remains a major clinical challenge. Aberrant HGF/c-MET upregulation and activation is frequently observed in bladder cancer correlating with cancer progression and invasion. However, the mechanisms underlying HGF/c-MET-mediated invasion in bladder cancer remains unknown. As part of a negative feedback loop SMAD7 binds to SMURF2 targeting the TGFβ receptor for degradation. Under these conditions, SMAD7 acts as a SMURF2 agonist by disrupting the intramolecular interactions within SMURF2. We demonstrate that HGF stimulates TGFβ signalling through c-SRC-mediated phosphorylation of SMURF2 resulting in loss of SMAD7 binding and enhanced SMURF2 C2-HECT interaction, inhibiting SMURF2 and enhancing TGFβ receptor stabilisation. This upregulation of the TGFβ pathway by HGF leads to TGFβ-mediated EMT and invasion. In vivo we show that TGFβ receptor inhibition prevents bladder cancer invasion. Furthermore, we make a rationale for the use of combinatorial TGFβ and MEK inhibitors for treatment of high-grade non-muscle-invasive bladder cancers.
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29
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Reversible regulation of SATB1 ubiquitination by USP47 and SMURF2 mediates colon cancer cell proliferation and tumor progression. Cancer Lett 2019; 448:40-51. [DOI: 10.1016/j.canlet.2019.01.039] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 01/26/2019] [Accepted: 01/29/2019] [Indexed: 02/07/2023]
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30
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Kim SY, Baek KH. TGF-β signaling pathway mediated by deubiquitinating enzymes. Cell Mol Life Sci 2019; 76:653-665. [PMID: 30349992 PMCID: PMC11105597 DOI: 10.1007/s00018-018-2949-y] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2018] [Revised: 09/27/2018] [Accepted: 10/15/2018] [Indexed: 12/18/2022]
Abstract
Ubiquitination is a reversible cellular process mediated by ubiquitin-conjugating enzymes, whereas deubiquitinating enzymes (DUBs) detach the covalently conjugated ubiquitin from target substrates to counter ubiquitination. DUBs play a crucial role in regulating various signal transduction pathways and biological processes including apoptosis, cell proliferation, DNA damage repair, metastasis, differentiation, etc. Since the transforming growth factor-β (TGF-β) signaling pathway participates in various cellular functions such as inflammation, metastasis and embryogenesis, aberrant regulation of TGF-β signaling induces abnormal cellular functions resulting in numerous diseases. This review focuses on DUBs regulating the TGF-β signaling pathway. We discuss the molecular mechanisms of DUBs involved in TGF-β signaling pathway, and biological and therapeutic implications for various diseases.
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Affiliation(s)
- Soo-Yeon Kim
- Department of Biomedical Science, CHA University, 335 Pangyo-Ro, Bundang-Gu, Seongnam, Gyeonggi, 13488, Republic of Korea
| | - Kwang-Hyun Baek
- Department of Biomedical Science, CHA University, 335 Pangyo-Ro, Bundang-Gu, Seongnam, Gyeonggi, 13488, Republic of Korea.
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31
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Teyra J, Singer AU, Schmitges FW, Jaynes P, Kit Leng Lui S, Polyak MJ, Fodil N, Krieger JR, Tong J, Schwerdtfeger C, Brasher BB, Ceccarelli DFJ, Moffat J, Sicheri F, Moran MF, Gros P, Eichhorn PJA, Lenter M, Boehmelt G, Sidhu SS. Structural and Functional Characterization of Ubiquitin Variant Inhibitors of USP15. Structure 2019; 27:590-605.e5. [PMID: 30713027 DOI: 10.1016/j.str.2019.01.002] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Revised: 10/23/2018] [Accepted: 12/31/2018] [Indexed: 12/12/2022]
Abstract
The multi-domain deubiquitinase USP15 regulates diverse eukaryotic processes and has been implicated in numerous diseases. We developed ubiquitin variants (UbVs) that targeted either the catalytic domain or each of three adaptor domains in USP15, including the N-terminal DUSP domain. We also designed a linear dimer (diUbV), which targeted the DUSP and catalytic domains, and exhibited enhanced specificity and more potent inhibition of catalytic activity than either UbV alone. In cells, the UbVs inhibited the deubiquitination of two USP15 substrates, SMURF2 and TRIM25, and the diUbV inhibited the effects of USP15 on the transforming growth factor β pathway. Structural analyses revealed that three distinct UbVs bound to the catalytic domain and locked the active site in a closed, inactive conformation, and one UbV formed an unusual strand-swapped dimer and bound two DUSP domains simultaneously. These inhibitors will enable the study of USP15 function in oncology, neurology, immunology, and inflammation.
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Affiliation(s)
- Joan Teyra
- The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Alex U Singer
- The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Frank W Schmitges
- The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Patrick Jaynes
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Sarah Kit Leng Lui
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Maria J Polyak
- Department of Biochemistry, McGill University, Montreal, QC, Canada; Corbin Therapeutics, Montreal, QC, Canada
| | - Nassima Fodil
- Department of Biochemistry, McGill University, Montreal, QC, Canada; Corbin Therapeutics, Montreal, QC, Canada
| | - Jonathan R Krieger
- SPARC BioCentre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada
| | - Jiefei Tong
- Cell Biology Program, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada
| | | | - Bradley B Brasher
- Boston Biochem, a Bio-Techne Brand, 840 Memorial Drive, Cambridge, MA 02139, USA
| | - Derek F J Ceccarelli
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada
| | - Jason Moffat
- The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Frank Sicheri
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Michael F Moran
- SPARC BioCentre, Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Cell Biology Program, The Hospital for Sick Children, 686 Bay Street, Toronto, ON M5G 0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Philippe Gros
- Department of Biochemistry, McGill University, Montreal, QC, Canada
| | - Pieter J A Eichhorn
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Martin Lenter
- Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
| | | | - Sachdev S Sidhu
- The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
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32
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Ward SJ, Gratton HE, Indrayudha P, Michavila C, Mukhopadhyay R, Maurer SK, Caulton SG, Emsley J, Dreveny I. The structure of the deubiquitinase USP15 reveals a misaligned catalytic triad and an open ubiquitin-binding channel. J Biol Chem 2018; 293:17362-17374. [PMID: 30228188 PMCID: PMC6231127 DOI: 10.1074/jbc.ra118.003857] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Revised: 09/13/2018] [Indexed: 12/24/2022] Open
Abstract
Ubiquitin-specific protease 15 (USP15) regulates important cellular processes, including transforming growth factor β (TGF-β) signaling, mitophagy, mRNA processing, and innate immune responses; however, structural information on USP15's catalytic domain is currently unavailable. Here, we determined crystal structures of the USP15 catalytic core domain, revealing a canonical USP fold, including a finger, palm, and thumb region. Unlike for the structure of paralog USP4, the catalytic triad is in an inactive configuration with the catalytic cysteine ∼10 Å apart from the catalytic histidine. This conformation is atypical, and a similar misaligned catalytic triad has so far been observed only for USP7, although USP15 and USP7 are differently regulated. Moreover, we found that the active-site loops are flexible, resulting in a largely open ubiquitin tail–binding channel. Comparison of the USP15 and USP4 structures points to a possible activation mechanism. Sequence differences between these two USPs mainly map to the S1′ region likely to confer specificity, whereas the S1 ubiquitin–binding pocket is highly conserved. Isothermal titration calorimetry monoubiquitin- and linear diubiquitin-binding experiments showed significant differences in their thermodynamic profiles, with USP15 displaying a lower affinity for monoubiquitin than USP4. Moreover, we report that USP15 is weakly inhibited by the antineoplastic agent mitoxantrone in vitro. A USP15–mitoxantrone complex structure disclosed that the anthracenedione interacts with the S1′ binding site. Our results reveal first insights into USP15's catalytic domain structure, conformational changes, differences between paralogs, and small-molecule interactions and establish a framework for cellular probe and inhibitor development.
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Affiliation(s)
- Stephanie J Ward
- From the Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom
| | - Hayley E Gratton
- From the Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom
| | - Peni Indrayudha
- From the Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom
| | - Camille Michavila
- From the Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom
| | - Rishov Mukhopadhyay
- From the Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom
| | - Sigrun K Maurer
- From the Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom
| | - Simon G Caulton
- From the Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom
| | - Jonas Emsley
- From the Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom
| | - Ingrid Dreveny
- From the Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, Nottingham NG7 2RD, United Kingdom
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33
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Saei A, Palafox M, Benoukraf T, Kumari N, Jaynes PW, Iyengar PV, Muñoz-Couselo E, Nuciforo P, Cortés J, Nötzel C, Kumarakulasinghe NB, Richard JLC, Bin Adam Isa ZF, Pang B, Guzman M, Siqin Z, Yang H, Tam WL, Serra V, Eichhorn PJA. Loss of USP28-mediated BRAF degradation drives resistance to RAF cancer therapies. J Exp Med 2018; 215:1913-1928. [PMID: 29880484 PMCID: PMC6028519 DOI: 10.1084/jem.20171960] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2017] [Revised: 03/09/2018] [Accepted: 05/09/2018] [Indexed: 11/04/2022] Open
Abstract
RAF kinase inhibitors are clinically active in patients with BRAF (V600E) mutant melanoma. However, rarely do tumors regress completely, with the majority of responses being short-lived. This is partially mediated through the loss of negative feedback loops after MAPK inhibition and reactivation of upstream signaling. Here, we demonstrate that the deubiquitinating enzyme USP28 functions through a feedback loop to destabilize RAF family members. Loss of USP28 stabilizes BRAF enhancing downstream MAPK activation and promotes resistance to RAF inhibitor therapy in culture and in vivo models. Importantly, we demonstrate that USP28 is deleted in a proportion of melanoma patients and may act as a biomarker for response to BRAF inhibitor therapy in patients. Furthermore, we identify Rigosertib as a possible therapeutic strategy for USP28-depleted tumors. Our results show that loss of USP28 enhances MAPK activity through the stabilization of RAF family members and is a key factor in BRAF inhibitor resistance.
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Affiliation(s)
- Azad Saei
- Genome Institute of Singapore, A*STAR, Singapore, Singapore
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Marta Palafox
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Touati Benoukraf
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Nishi Kumari
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | | | | | | | - Paolo Nuciforo
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Javier Cortés
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Cancer Ramon y Cajal University Hospital, Madrid, Spain
- IOB Institute of Oncology, Quironsalud group, Madrid & Barcelona, Spain
| | - Christopher Nötzel
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Nesaretnam Barr Kumarakulasinghe
- Department of Hematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore, Singapore
| | | | | | - Brendan Pang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Marta Guzman
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Zhou Siqin
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Henry Yang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Wai Leong Tam
- Genome Institute of Singapore, A*STAR, Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Violeta Serra
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Pieter Johan Adam Eichhorn
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- School of Pharmacy and Biomedical Sciences, Curtin University, Perth, Australia
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Hrdinka M, Gyrd-Hansen M. The Met1-Linked Ubiquitin Machinery: Emerging Themes of (De)regulation. Mol Cell 2017; 68:265-280. [PMID: 29053955 DOI: 10.1016/j.molcel.2017.09.001] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Revised: 07/21/2017] [Accepted: 08/31/2017] [Indexed: 01/24/2023]
Abstract
The linear ubiquitin chain assembly complex, LUBAC, is the only known mammalian ubiquitin ligase that makes methionine 1 (Met1)-linked polyubiquitin (also referred to as linear ubiquitin). A decade after LUBAC was discovered as a cellular activity of unknown function, there are now many lines of evidence connecting Met1-linked polyubiquitin to NF-κB signaling, cell death, inflammation, immunity, and cancer. We now know that Met1-linked polyubiquitin has potent signaling functions and that its deregulation is connected to disease. Indeed, mutations and deficiencies in several factors involved in conjugation and deconjugation of Met1-linked polyubiquitin have been implicated in immune-related disorders. Here, we discuss current knowledge and recent insights into the role and regulation of Met1-linked polyubiquitin, with an emphasis on the mechanisms controlling the function of LUBAC.
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Affiliation(s)
- Matous Hrdinka
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK
| | - Mads Gyrd-Hansen
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Old Road Campus Research Building, Oxford OX3 7DQ, UK.
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35
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Kumari N, Jaynes PW, Saei A, Iyengar PV, Richard JLC, Eichhorn PJA. The roles of ubiquitin modifying enzymes in neoplastic disease. Biochim Biophys Acta Rev Cancer 2017; 1868:456-483. [PMID: 28923280 DOI: 10.1016/j.bbcan.2017.09.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 09/11/2017] [Accepted: 09/12/2017] [Indexed: 12/22/2022]
Abstract
The initial experiments performed by Rose, Hershko, and Ciechanover describing the identification of a specific degradation signal in short-lived proteins paved the way to the discovery of the ubiquitin mediated regulation of numerous physiological functions required for cellular homeostasis. Since their discovery of ubiquitin and ubiquitin function over 30years ago it has become wholly apparent that ubiquitin and their respective ubiquitin modifying enzymes are key players in tumorigenesis. The human genome encodes approximately 600 putative E3 ligases and 80 deubiquitinating enzymes and in the majority of cases these enzymes exhibit specificity in sustaining either pro-tumorigenic or tumour repressive responses. In this review, we highlight the known oncogenic and tumour suppressive effects of ubiquitin modifying enzymes in cancer relevant pathways with specific focus on PI3K, MAPK, TGFβ, WNT, and YAP pathways. Moreover, we discuss the capacity of targeting DUBs as a novel anticancer therapeutic strategy.
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Affiliation(s)
- Nishi Kumari
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
| | - Patrick William Jaynes
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore
| | - Azad Saei
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore; Genome Institute of Singapore, A*STAR, Singapore
| | | | | | - Pieter Johan Adam Eichhorn
- Cancer Science Institute of Singapore, National University of Singapore, 117599, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
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36
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Deubiquitylating enzymes in receptor endocytosis and trafficking. Biochem J 2017; 473:4507-4525. [PMID: 27941029 DOI: 10.1042/bcj20160826] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 09/15/2016] [Accepted: 09/16/2016] [Indexed: 12/25/2022]
Abstract
In recent times, our knowledge of the roles ubiquitin plays in multiple cellular processes has expanded exponentially, with one example being the role of ubiquitin in receptor endocytosis and trafficking. This has prompted a multitude of studies examining how the different machinery involved in the addition and removal of ubiquitin can influence this process. Multiple deubiquitylating enzymes (DUBs) have been implicated either in facilitating receptor endocytosis and lysosomal degradation or in rescuing receptor levels by preventing endocytosis and/or promoting recycling to the plasma membrane. In this review, we will discuss in detail what is currently known about the role of DUBs in regulating the endocytosis of various transmembrane receptors and ion channels. We will also expand upon the role DUBs play in receptor sorting at the multivesicular body to determine whether a receptor is recycled or trafficked to the lysosome for degradation. Finally, we will briefly discuss how the DUBs implicated in these processes may contribute to the pathogenesis of a range of diseases, and thus the potential these have as therapeutic targets.
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37
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Iyengar PV. Regulation of Ubiquitin Enzymes in the TGF-β Pathway. Int J Mol Sci 2017; 18:ijms18040877. [PMID: 28425962 PMCID: PMC5412458 DOI: 10.3390/ijms18040877] [Citation(s) in RCA: 32] [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: 03/24/2017] [Revised: 04/15/2017] [Accepted: 04/18/2017] [Indexed: 02/07/2023] Open
Abstract
The transforming growth factor-β (TGF-β) pathway has a tumor suppressor role in normal and premalignant cells but promotes oncogenesis in advanced cancer cells. Components of the pathway are tightly controlled by ubiquitin modifying enzymes and aberrations in these enzymes are frequently observed to dysregulate the pathway causing diseases such as bone disorders, cancer and metastasis. These enzymes and their counterparts are increasingly being tested as druggable targets, and thus a deeper understanding of the enzymes is required. This review summarizes the roles of specific ubiquitin modifying enzymes in the TGF-β pathway and how they are regulated.
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38
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Kit Leng Lui S, Iyengar PV, Jaynes P, Isa ZFBA, Pang B, Tan TZ, Eichhorn PJA. USP26 regulates TGF-β signaling by deubiquitinating and stabilizing SMAD7. EMBO Rep 2017; 18:797-808. [PMID: 28381482 PMCID: PMC5412796 DOI: 10.15252/embr.201643270] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2016] [Revised: 03/08/2017] [Accepted: 03/08/2017] [Indexed: 01/09/2023] Open
Abstract
The amplitude of transforming growth factor-β (TGF-β) signal is tightly regulated to ensure appropriate physiological responses. As part of negative feedback loop SMAD7, a direct transcriptional target of downstream TGF-β signaling acts as a scaffold to recruit the E3 ligase SMURF2 to target the TGF-β receptor complex for ubiquitin-mediated degradation. Here, we identify the deubiquitinating enzyme USP26 as a novel integral component of this negative feedback loop. We demonstrate that TGF-β rapidly enhances the expression of USP26 and reinforces SMAD7 stability by limiting the ubiquitin-mediated turnover of SMAD7. Conversely, knockdown of USP26 rapidly degrades SMAD7 resulting in TGF-β receptor stabilization and enhanced levels of p-SMAD2. Clinically, loss of USP26 correlates with high TGF-β activity and confers poor prognosis in glioblastoma. Our data identify USP26 as a novel negative regulator of the TGF-β pathway and suggest that loss of USP26 expression may be an important factor in glioblastoma pathogenesis.
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Affiliation(s)
- Sarah Kit Leng Lui
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | | | - Patrick Jaynes
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | | | - Brendan Pang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Pieter Johan Adam Eichhorn
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore .,Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
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The Regulations of Deubiquitinase USP15 and Its Pathophysiological Mechanisms in Diseases. Int J Mol Sci 2017; 18:ijms18030483. [PMID: 28245560 PMCID: PMC5372499 DOI: 10.3390/ijms18030483] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2017] [Revised: 02/14/2017] [Accepted: 02/18/2017] [Indexed: 02/06/2023] Open
Abstract
Deubiquitinases (DUBs) play a critical role in ubiquitin-directed signaling by catalytically removing the ubiquitin from substrate proteins. Ubiquitin-specific protease 15 (USP15), a member of the largest subfamily of cysteine protease DUBs, contains two conservative cysteine (Cys) and histidine (His) boxes. USP15 harbors two zinc-binding motifs that are essential for recognition of poly-ubiquitin chains. USP15 is grouped into the same category with USP4 and USP11 due to high degree of homology in an N-terminal region consisting of domains present in ubiquitin-specific proteases (DUSP) domain and ubiquitin-like (UBL) domain. USP15 cooperates with COP9 signalosome complex (CSN) to maintain the stability of cullin-ring ligase (CRL) adaptor proteins by removing the conjugated ubiquitin chains from RBX1 subunit of CRL. USP15 is also implicated in the stabilization of the human papillomavirus type 16 E6 oncoprotein, adenomatous polyposis coli, and IκBα. Recently, reports have suggested that USP15 acts as a key regulator of TGF-β receptor-signaling pathways by deubiquitinating the TGF-β receptor itself and its downstream transducers receptor-regulated SMADs (R-SMADs), including SMAD1, SMAD2, and SMAD3, thus activating the TGF-β target genes. Although the importance of USP15 in pathologic processes remains ambiguous so far, in this review, we endeavor to summarize the literature regarding the relationship of the deubiquitinating action of USP15 with the proteins involved in the regulation of Parkinson’s disease, virus infection, and cancer-related signaling networks.
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Bingol B, Sheng M. Mechanisms of mitophagy: PINK1, Parkin, USP30 and beyond. Free Radic Biol Med 2016; 100:210-222. [PMID: 27094585 DOI: 10.1016/j.freeradbiomed.2016.04.015] [Citation(s) in RCA: 222] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 04/15/2016] [Accepted: 04/15/2016] [Indexed: 12/16/2022]
Abstract
Mitochondrial quality control is central for maintaining a healthy population of mitochondria. Two Parkinson's disease genes, mitochondrial kinase PINK1 and ubiquitin ligase Parkin, degrade damaged mitochondria though mitophagy. In this pathway, PINK1 senses mitochondrial damage and activates Parkin by phosphorylating Parkin and ubiquitin. Activated Parkin then builds ubiquitin chains on damaged mitochondria to tag them for degradation in lysosomes. USP30 deubiquitinase acts as a brake on mitophagy by opposing Parkin-mediated ubiquitination. Human genetic data point to a role for mitophagy defects in neurodegenerative diseases. This review highlights the molecular mechanisms of the mitophagy pathway and the recent advances in the understanding of mitophagy in vivo.
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Affiliation(s)
- Baris Bingol
- Department of Neuroscience, Genentech Inc, South San Francisco, CA 94080, USA.
| | - Morgan Sheng
- Department of Neuroscience, Genentech Inc, South San Francisco, CA 94080, USA
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USP15 regulates type I interferon response and is required for pathogenesis of neuroinflammation. Nat Immunol 2016; 18:54-63. [DOI: 10.1038/ni.3581] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 08/25/2016] [Indexed: 12/21/2022]
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Liu S, de Boeck M, van Dam H, ten Dijke P. Regulation of the TGF-β pathway by deubiquitinases in cancer. Int J Biochem Cell Biol 2016; 76:135-45. [DOI: 10.1016/j.biocel.2016.05.001] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 05/02/2016] [Accepted: 05/03/2016] [Indexed: 11/26/2022]
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Qian G, Ren Y, Zuo Y, Yuan Y, Zhao P, Wang X, Cheng Q, Liu J, Zhang L, Guo T, Liu C, Zheng H. Smurf1 represses TNF-α production through ubiquitination and destabilization of USP5. Biochem Biophys Res Commun 2016; 474:491-496. [DOI: 10.1016/j.bbrc.2016.04.135] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Accepted: 04/26/2016] [Indexed: 02/02/2023]
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