|
1
|
Kitaya K. B Cell Lineage in the Human Endometrium: Physiological and Pathological Implications. Cells 2025; 14:648. [PMID: 40358172 PMCID: PMC12071375 DOI: 10.3390/cells14090648] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2025] [Revised: 04/12/2025] [Accepted: 04/26/2025] [Indexed: 05/15/2025] Open
Abstract
Immunocompetent cells of B lineage function in the humoral immunity system in the adaptive immune responses. B cells differentiate into plasmacytes upon antigen-induced activation and produce different subclasses of immunoglobulins/antibodies. Secreted immunoglobulins not only interact with pathogens to inactivate and neutralize them, but also involve the complement system to exert antibacterial activities and trigger opsonization. Endometrium is a mucosal tissue that lines the mammalian uterus and is indispensable for the establishment of a successful pregnancy. The lymphocytes of B cell lineage are a minority in the human cycling endometrium. Human endometrial B cells have therefore been understudied so far. However, the disorders of the female reproductive tract, including chronic endometritis and endometriosis, have highlighted the importance of further research on the endometrial B cell lineage. This review aims to revisit lymphopoiesis, maturation, commitment, and survival of B cells, shedding light on their physiological and pathological implications in the human endometrium.
Collapse
Affiliation(s)
- Kotaro Kitaya
- Infertility Center, Iryouhoujin Kouseikai Mihara Hospital, 6-8 Kamikatsura Miyanogo-cho, Nishikyo-ku, Kyoto 615-8227, Japan
| |
Collapse
|
|
2
|
Xiong S, Zhou J, Tan TK, Chung TH, Tan TZ, Toh SHM, Tang NXN, Jia Y, See YX, Fullwood MJ, Sanda T, Chng WJ. Super enhancer acquisition drives expression of oncogenic PPP1R15B that regulates protein homeostasis in multiple myeloma. Nat Commun 2024; 15:6810. [PMID: 39122682 PMCID: PMC11316114 DOI: 10.1038/s41467-024-50910-z] [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: 06/30/2023] [Accepted: 07/25/2024] [Indexed: 08/12/2024] Open
Abstract
Multiple myeloma is a hematological malignancy arising from immunoglobulin-secreting plasma cells. It remains poorly understood how chromatin rewiring of regulatory elements contributes to tumorigenesis and therapy resistance in myeloma. Here we generate a high-resolution contact map of myeloma-associated super-enhancers by integrating H3K27ac ChIP-seq and HiChIP from myeloma cell lines, patient-derived myeloma cells and normal plasma cells. Our comprehensive transcriptomic and phenomic analyses prioritize candidate genes with biological and clinical implications in myeloma. We show that myeloma cells frequently acquire SE that transcriptionally activate an oncogene PPP1R15B, which encodes a regulatory subunit of the holophosphatase complex that dephosphorylates translation initiation factor eIF2α. Epigenetic silencing or knockdown of PPP1R15B activates pro-apoptotic eIF2α-ATF4-CHOP pathway, while inhibiting protein synthesis and immunoglobulin production. Pharmacological inhibition of PPP1R15B using Raphin1 potentiates the anti-myeloma effect of bortezomib. Our study reveals that myeloma cells are vulnerable to perturbation of PPP1R15B-dependent protein homeostasis, highlighting a promising therapeutic strategy.
Collapse
Affiliation(s)
- Sinan Xiong
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Jianbiao Zhou
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
| | - Tze King Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Tae-Hoon Chung
- 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
| | - Sabrina Hui-Min Toh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Nicole Xin Ning Tang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Yunlu Jia
- Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China
| | - Yi Xiang See
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Melissa Jane Fullwood
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- School of Biological Sciences, Nanyang Technological University, Singapore, Singapore
- Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore
| | - Takaomi Sanda
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Wee-Joo Chng
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
- NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
- Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), National University Health System (NUHS), Singapore, Singapore.
| |
Collapse
|
|
3
|
Sogawa A, Komori R, Yanagitani K, Ohfurudono M, Tsuru A, Kadoi K, Kimata Y, Yoshida H, Kohno K. Signal sequence-triage is activated by translocon obstruction sensed by an ER stress sensor IRE1α. Cell Struct Funct 2023; 48:211-221. [PMID: 37766570 PMCID: PMC11496779 DOI: 10.1247/csf.23072] [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: 11/18/2022] [Accepted: 09/24/2023] [Indexed: 09/29/2023] Open
Abstract
Secretory pathway proteins are cotranslationally translocated into the endoplasmic reticulum (ER) of metazoan cells through the protein channel, translocon. Given that there are far fewer translocons than ribosomes in a cell, it is essential that secretory protein-translating ribosomes only occupy translocons transiently. Therefore, if translocons are obstructed by ribosomes stalled or slowed in translational elongation, it possibly results in deleterious consequences to cellular function. Hence, we investigated how translocon clogging by stalled ribosomes affects mammalian cells. First, we constructed ER-destined translational arrest proteins (ER-TAP) as an artificial protein that clogged the translocon in the ER membrane. Here, we show that the translocon clogging by ER-TAP expression activates triage of signal sequences (SS) in which secretory pathway proteins harboring highly efficient SS are preferentially translocated into the ER lumen. Interestingly, the translocon obstructed status specifically activates inositol requiring enzyme 1α (IRE1α) but not protein kinase R-like ER kinase (PERK). Given that the IRE1α-XBP1 pathway mainly induces the translocon components, our discovery implies that lowered availability of translocon activates IRE1α, which induces translocon itself. This results in rebalance between protein influx into the ER and the cellular translocation capacity.Key words: endoplasmic reticulum, translocation capacity, translocon clogging, IRE1, signal sequence.
Collapse
Affiliation(s)
- Ashuei Sogawa
- Laboratory of Molecular and Cell Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
- Osaka International Cancer Institute (OICI), 3-1-69 Otemae, Chuo-ku, Osaka, Osaka 541-8567, Japan
| | - Ryota Komori
- Institute for Research Initiatives, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
- Department of Biochemistry and Molecular Biology, Graduate School of Science, University of Hyogo, Harima Science Garden City, Hyogo 678-1297, Japan
| | - Kota Yanagitani
- Institute for Research Initiatives, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
- Ubiquitin Biology Laboratory, Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Miku Ohfurudono
- Laboratory of Molecular and Cell Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
- Institute for Research Initiatives, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
| | - Akio Tsuru
- Laboratory of Molecular and Cell Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
- Institute for Research Initiatives, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
| | - Koji Kadoi
- Laboratory of Molecular and Cell Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
| | - Yukio Kimata
- Laboratory of Molecular and Cell Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
| | - Hiderou Yoshida
- Department of Biochemistry and Molecular Biology, Graduate School of Science, University of Hyogo, Harima Science Garden City, Hyogo 678-1297, Japan
| | - Kenji Kohno
- Laboratory of Molecular and Cell Genetics, Graduate School of Biological Sciences, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
- Institute for Research Initiatives, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
- Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology (NAIST), 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
- Department of Biochemistry and Molecular Biology, Graduate School of Science, University of Hyogo, Harima Science Garden City, Hyogo 678-1297, Japan
| |
Collapse
|
|
4
|
Di Conza G, Ho PC, Cubillos-Ruiz JR, Huang SCC. Control of immune cell function by the unfolded protein response. Nat Rev Immunol 2023; 23:546-562. [PMID: 36755160 DOI: 10.1038/s41577-023-00838-0] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/13/2023] [Indexed: 02/10/2023]
Abstract
Initiating and maintaining optimal immune responses requires high levels of protein synthesis, folding, modification and trafficking in leukocytes, which are processes orchestrated by the endoplasmic reticulum. Importantly, diverse extracellular and intracellular conditions can compromise the protein-handling capacity of this organelle, inducing a state of 'endoplasmic reticulum stress' that activates the unfolded protein response (UPR). Emerging evidence shows that physiological or pathological activation of the UPR can have effects on immune cell survival, metabolism, function and fate. In this Review, we discuss the canonical role of the adaptive UPR in immune cells and how dysregulation of this pathway in leukocytes contributes to diverse pathologies such as cancer, autoimmunity and metabolic disorders. Furthermore, we provide an overview as to how pharmacological approaches that modulate the UPR could be harnessed to control or activate immune cell function in disease.
Collapse
Affiliation(s)
- Giusy Di Conza
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland
| | - Ping-Chih Ho
- Department of Fundamental Oncology, University of Lausanne, Lausanne, Switzerland.
- Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.
| | - Juan R Cubillos-Ruiz
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA.
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
- Immunology and Microbial Pathogenesis Program, Graduate School of Medical Sciences, Weill Cornell Medicine, New York, NY, USA.
| | - Stanley Ching-Cheng Huang
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
- Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
| |
Collapse
|
|
5
|
Li HY, Huang LF, Huang XR, Wu D, Chen XC, Tang JX, An N, Liu HF, Yang C. Endoplasmic Reticulum Stress in Systemic Lupus Erythematosus and Lupus Nephritis: Potential Therapeutic Target. J Immunol Res 2023; 2023:7625817. [PMID: 37692838 PMCID: PMC10484658 DOI: 10.1155/2023/7625817] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 07/20/2023] [Accepted: 08/10/2023] [Indexed: 09/12/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease. Approximately one-third to two-thirds of the patients with SLE progress to lupus nephritis (LN). The pathogenesis of SLE and LN has not yet been fully elucidated, and effective treatment for both conditions is lacking. The endoplasmic reticulum (ER) is the largest intracellular organelle and is a site of protein synthesis, lipid metabolism, and calcium storage. Under stress, the function of ER is disrupted, and the accumulation of unfolded or misfolded proteins occurs in ER, resulting in an ER stress (ERS) response. ERS is involved in the dysfunction of B cells, macrophages, T cells, dendritic cells, neutrophils, and other immune cells, causing immune system disorders, such as SLE. In addition, ERS is also involved in renal resident cell injury and contributes to the progression of LN. The molecular chaperones, autophagy, and proteasome degradation pathways inhibit ERS and restore ER homeostasis to improve the dysfunction of immune cells and renal resident cell injury. This may be a therapeutic strategy for SLE and LN. In this review, we summarize advances in this field.
Collapse
Affiliation(s)
- Hui-Yuan Li
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Li-Feng Huang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Xiao-Rong Huang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Dan Wu
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Xiao-Cui Chen
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Ji-Xin Tang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Ning An
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Hua-Feng Liu
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| | - Chen Yang
- Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
| |
Collapse
|
|
6
|
Haas M, Fest T. Final step of B-cell differentiation into plasmablasts; the right time to activate plasma cell PIM2 kinase. Immunol Lett 2023; 258:45-50. [PMID: 37207916 DOI: 10.1016/j.imlet.2023.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 05/13/2023] [Accepted: 05/16/2023] [Indexed: 05/21/2023]
Abstract
The differentiation of B cells into antibody-secreting plasma cells is a complex process that involves extensive changes in morphology, lifespan, and cellular metabolism to support the high rates of antibody production. During the final stage of differentiation, B cells undergo significant expansion of their endoplasmic reticulum and mitochondria, which induces cellular stress and may lead to cell death in absence of effective inhibition of the apoptotic pathway. These changes are tightly regulated at transcriptional and epigenetic levels, as well as at post-translational level, with protein modifications playing a critical role in the process of cellular modification and adaptation. Our recent research has highlighted the pivotal role of the serine/threonine kinase PIM2 in B cell differentiation, from commitment stage to plasmablast and maintenance of expression in mature plasma cells. PIM2 has been shown to promote cell cycle progression during the final stage of differentiation and to inhibit Caspase 3 activation, raising the threshold for apoptosis. In this review, we examine the key molecular mechanisms controlled by PIM2 that contribute to plasma cell development and maintenance.
Collapse
Affiliation(s)
- Marion Haas
- Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, Team B_DEVIL, UMR_S1236, Rennes, France; Laboratoire d'Hématologie, Centre Hospitalier Universitaire, Rennes, France
| | - Thierry Fest
- Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, Team B_DEVIL, UMR_S1236, Rennes, France; Laboratoire d'Hématologie, Centre Hospitalier Universitaire, Rennes, France.
| |
Collapse
|
|
7
|
Xiong E, Popp O, Salomon C, Mertins P, Kocks C, Rajewsky K, Chu VT. A CRISPR/Cas9-mediated screen identifies determinants of early plasma cell differentiation. Front Immunol 2023; 13:1083119. [PMID: 36685499 PMCID: PMC9849354 DOI: 10.3389/fimmu.2022.1083119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 12/12/2022] [Indexed: 01/06/2023] Open
Abstract
Introduction The differentiation of B cells into antibody-secreting plasma cells depends on cell division-coupled, epigenetic and other cellular processes that are incompletely understood. Methods We have developed a CRISPR/Cas9-based screen that models an early stage of T cell-dependent plasma cell differentiation and measures B cell survival or proliferation versus the formation of CD138+ plasmablasts. Here, we refined and extended this screen to more than 500 candidate genes that are highly expressed in plasma cells. Results Among known genes whose deletion preferentially or mostly affected plasmablast formation were the transcription factors Prdm1 (BLIMP1), Irf4 and Pou2af1 (OBF-1), and the Ern1 gene encoding IRE1a, while deletion of XBP1, the transcriptional master regulator that specifies the expansion of the secretory program in plasma cells, had no effect. Defective plasmablast formation caused by Ern1 deletion could not be rescued by the active, spliced form of XBP1 whose processing is dependent on and downstream of IRE1a, suggesting that in early plasma cell differentiation IRE1a acts independently of XBP1. Moreover, we newly identified several genes involved in NF-kB signaling (Nfkbia), vesicle trafficking (Arf4, Preb) and epigenetic regulators that form part of the NuRD complex (Hdac1, Mta2, Mbd2) to be required for plasmablast formation. Deletion of ARF4, a small GTPase required for COPI vesicle formation, impaired plasmablast formation and blocked antibody secretion. After Hdac1 deletion plasmablast differentiation was consistently reduced by about 50%, while deletion of the closely related Hdac2 gene had no effect. Hdac1 knock-out led to strongly perturbed protein expression of antagonistic transcription factors that govern plasma cell versus B cell identity (by decreasing IRF4 and BLIMP1 and increasing BACH2 and PAX5). Discussion Taken together, our results highlight specific and non-redundant roles for Ern1, Arf4 and Hdac1 in the early steps of plasma cell differentiation.
Collapse
Affiliation(s)
- Ermeng Xiong
- Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Oliver Popp
- Proteomics platform, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC) and Berlin Institute of Health (BIH), Berlin, Germany
| | - Claudia Salomon
- Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Philipp Mertins
- Proteomics platform, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC) and Berlin Institute of Health (BIH), Berlin, Germany
| | - Christine Kocks
- Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany,Genome Engineering & Disease Models, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Klaus Rajewsky
- Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany,*Correspondence: Klaus Rajewsky, ; Van Trung Chu,
| | - Van Trung Chu
- Immune Regulation and Cancer, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany,Genome Engineering & Disease Models, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany,*Correspondence: Klaus Rajewsky, ; Van Trung Chu,
| |
Collapse
|
|
8
|
Mountz JD, Gao M, Ponder DM, Liu S, Sun CW, Alduraibi F, Sullivan K, Pat B, Dell'Italia LJ, Hsu HC. IL-4 receptor blockade is a global repressor of naïve B cell development and responses in a dupilumab-treated patient. Clin Immunol 2022; 244:109130. [PMID: 36189576 PMCID: PMC9741950 DOI: 10.1016/j.clim.2022.109130] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Revised: 09/14/2022] [Accepted: 09/14/2022] [Indexed: 12/14/2022]
Abstract
Here, we report a case of atopic dermatitis (AD) in a patient who received biweekly doses of dupilumab, an antibody against the IL-4 receptor α chain (IL-4Rα). Single cell RNA-sequencing showed that naïve B cells expressed the highest levels of IL4R compared to other B cell subpopulations. Compared to controls, the dupilumab-treated patient exhibited diminished percentages of IL4R+IGHD+ naïve B cells and down-regulation of IL4R, FCER2 (CD23), and IGHD. Dupilumab treatment resulted in upregulation of genes associated with apoptosis and inhibition of B cell receptor signaling and down-regulation of class-switch and memory B cell development genes. The dupilumab-treated patient exhibited a rapid decline in COVID-19 anti-spike and anti-receptor binding domain antibodies between 4 and 8 and 11 months post COVID-19 vaccination. Our data suggest that intact and persistent IL-4 signaling is necessary for maintaining robust survival and development of naïve B cells, and maintaining a long term vaccine response.
Collapse
Affiliation(s)
- John D Mountz
- Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, USA; Department of Veterans Affairs Health Care System, Birmingham, AL, USA.
| | - Min Gao
- Informatics Institute, The University of Alabama at Birmingham, USA
| | - David M Ponder
- Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, USA
| | - Shanrun Liu
- Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, USA
| | - Chiao-Wang Sun
- Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, USA
| | - Fatima Alduraibi
- Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, USA
| | - Kathryn Sullivan
- Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, USA
| | - Betty Pat
- Department of Veterans Affairs Health Care System, Birmingham, AL, USA; Department of Medicine, Division of Cardiovascular Disease, the University of Alabama at Birmingham, Birmingham, AL, USA
| | - Louis J Dell'Italia
- Department of Veterans Affairs Health Care System, Birmingham, AL, USA; Department of Medicine, Division of Cardiovascular Disease, the University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hui-Chen Hsu
- Division of Clinical Immunology and Rheumatology, Department of Medicine, The University of Alabama at Birmingham, USA.
| |
Collapse
|
|
9
|
Vivas W, Weis S. Tidy up - The unfolded protein response in sepsis. Front Immunol 2022; 13:980680. [PMID: 36341413 PMCID: PMC9632622 DOI: 10.3389/fimmu.2022.980680] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2022] [Accepted: 10/06/2022] [Indexed: 11/23/2022] Open
Abstract
Pathogens, their toxic byproducts, and the subsequent immune reaction exert different forms of stress and damage to the tissue of the infected host. This stress can trigger specific transcriptional and post-transcriptional programs that have evolved to limit the pathogenesis of infectious diseases by conferring tissue damage control. If these programs fail, infectious diseases can take a severe course including organ dysfunction and damage, a phenomenon that is known as sepsis and which is associated with high mortality. One of the key adaptive mechanisms to counter infection-associated stress is the unfolded protein response (UPR), aiming to reduce endoplasmic reticulum stress and restore protein homeostasis. This is mediated via a set of diverse and complementary mechanisms, i.e. the reduction of protein translation, increase of protein folding capacity, and increase of polyubiquitination of misfolded proteins and subsequent proteasomal degradation. However, UPR is not exclusively beneficial since its enhanced or prolonged activation might lead to detrimental effects such as cell death. Thus, fine-tuning and time-restricted regulation of the UPR should diminish disease severity of infectious disease and improve the outcome of sepsis while not bearing long-term consequences. In this review, we describe the current knowledge of the UPR, its role in infectious diseases, regulation mechanisms, and further clinical implications in sepsis.
Collapse
Affiliation(s)
- Wolfgang Vivas
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Friedrich Schiller University, Jena, Germany
- Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Jena, Germany
- *Correspondence: Wolfgang Vivas,
| | - Sebastian Weis
- Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital, Friedrich Schiller University, Jena, Germany
- Leibniz Institute for Natural Product Research and Infection Biology-Hans Knöll Institute (HKI), Jena, Germany
- Institute for Infectious Disease and Infection Control, Jena University Hospital, Friedrich Schiller University, Jena, Germany
- Center for Sepsis Control and Care, Jena University Hospital, Friedrich Schiller University, Jena, Germany
| |
Collapse
|
|
10
|
Wiseman RL, Mesgarzadeh JS, Hendershot LM. Reshaping endoplasmic reticulum quality control through the unfolded protein response. Mol Cell 2022; 82:1477-1491. [PMID: 35452616 PMCID: PMC9038009 DOI: 10.1016/j.molcel.2022.03.025] [Citation(s) in RCA: 214] [Impact Index Per Article: 71.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 02/28/2022] [Accepted: 03/18/2022] [Indexed: 01/09/2023]
Abstract
Endoplasmic reticulum quality control (ERQC) pathways comprising chaperones, folding enzymes, and degradation factors ensure the fidelity of ER protein folding and trafficking to downstream secretory environments. However, multiple factors, including tissue-specific secretory proteomes, environmental and genetic insults, and organismal aging, challenge ERQC. Thus, a key question is: how do cells adapt ERQC to match the diverse, ever-changing demands encountered during normal physiology and in disease? The answer lies in the unfolded protein response (UPR), a signaling mechanism activated by ER stress. In mammals, the UPR comprises three signaling pathways regulated downstream of the ER membrane proteins IRE1, ATF6, and PERK. Upon activation, these UPR pathways remodel ERQC to alleviate cellular stress and restore ER function. Here, we describe how UPR signaling pathways adapt ERQC, highlighting their importance for maintaining ER function across tissues and the potential for targeting the UPR to mitigate pathologies associated with protein misfolding diseases.
Collapse
Affiliation(s)
- R. Luke Wiseman
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037,To whom correspondences should be addressed: Linda Hendershot, ; R. Luke Wiseman,
| | - Jaleh S. Mesgarzadeh
- Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037
| | - Linda M. Hendershot
- Department of Tumor Biology, St Jude Children’s Research Hospital, Memphis, TN 38105,To whom correspondences should be addressed: Linda Hendershot, ; R. Luke Wiseman,
| |
Collapse
|
|
11
|
Zhu H, Jiang C, Kaufman RJ, Li H, Singh N. In Vitro Stimulation of IRE1α/XBP1-Deficient B Cells with LPS. Methods Mol Biol 2022; 2378:221-231. [PMID: 34985703 PMCID: PMC9382655 DOI: 10.1007/978-1-0716-1732-8_14] [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] [Indexed: 01/03/2023]
Abstract
During immune responses, pathogen-specific B cells differentiate into plasma cells. Plasma cells synthesize and secrete large amounts of immunoglobulin (Ig) molecules which play a central role in immunity against pathogens. The synthesis, proper folding, and secretion of these Ig molecules require expansion of the extensive endoplasmic reticulum (ER) network. Accumulation of unfolded or misfolded proteins in the ER is sensed by three sensors: IRE1/XBP1, PERK, and ATF6, which coordinate with each other and initiate the unfolded protein response (UPR) pathway to expand the ER network and its protein folding and secretion capability. The expansion and maintenance of the ER network in plasma cells is triggered by activation of the IRE1/XBP1 branch of the UPR pathway. Here, we discuss the methods to stimulate the differentiation of B cells into plasma cells, measure the activation of the XBP1 pathway, and quantify the ER network.
Collapse
Affiliation(s)
- Huabin Zhu
- Department of Biochemistry and Molecular Biology, Georgia Cancer Center, Augusta University, August, GA, USA
| | - Chen Jiang
- Department of Biochemistry and Molecular Biology, Georgia Cancer Center, Augusta University, August, GA, USA
| | - Randal J Kaufman
- Degenerative Diseases Program, Sanford Burnham Prebys, Medical Discovery Institute, La Jolla, CA, USA
| | - Honglin Li
- Department of Biochemistry and Molecular Biology, Georgia Cancer Center, Augusta University, August, GA, USA
| | - Nagendra Singh
- Department of Biochemistry and Molecular Biology, Georgia Cancer Center, Augusta University, August, GA, USA.
| |
Collapse
|
|
12
|
Nguyen DC, Duan M, Ali M, Ley A, Sanz I, Lee FEH. Plasma cell survival: The intrinsic drivers, migratory signals, and extrinsic regulators. Immunol Rev 2021; 303:138-153. [PMID: 34337772 PMCID: PMC8387437 DOI: 10.1111/imr.13013] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Accepted: 07/13/2021] [Indexed: 12/13/2022]
Abstract
Antibody-secreting cells (ASC) are the effectors of protective humoral immunity and the only cell type that produces antibodies or immunoglobulins in mammals. In addition to their formidable capacity to secrete massive quantities of proteins, ASC are terminally differentiated and have unique features to become long-lived plasma cells (LLPC). Upon antigen encounter, B cells are activated through a complex multistep process to undergo fundamental morphological, subcellular, and molecular transformation to become an efficient protein factory with lifelong potential. The ASC survival potential is determined by factors at the time of induction, capacity to migration from induction to survival sites, and ability to mature in the specialized bone marrow microenvironments. In the past decade, considerable progress has been made in identifying factors regulating ASC longevity. Here, we review the intrinsic drivers, trafficking signals, and extrinsic regulators with particular focus on how they impact the survival potential to become a LLPC.
Collapse
Affiliation(s)
- Doan C. Nguyen
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, United States
| | - Meixue Duan
- School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, United States
| | - Mohammad Ali
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, United States
| | - Ariel Ley
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, United States
| | - Ignacio Sanz
- Division of Rheumatology, Department of Medicine, Emory University, Atlanta, GA, United States
- Lowance Center for Human Immunology, Emory University, Atlanta, GA, United States
| | - F. Eun-Hyung Lee
- Division of Pulmonary, Allergy, Critical Care, and Sleep Medicine, Department of Medicine, Emory University, Atlanta, GA, United States
- Lowance Center for Human Immunology, Emory University, Atlanta, GA, United States
| |
Collapse
|
|
13
|
Patterson DG, Kania AK, Zuo Z, Scharer CD, Boss JM. Epigenetic gene regulation in plasma cells. Immunol Rev 2021; 303:8-22. [PMID: 34010461 PMCID: PMC8387415 DOI: 10.1111/imr.12975] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 04/23/2021] [Indexed: 12/12/2022]
Abstract
Humoral immunity provides protection from pathogenic infection and is mediated by antibodies following the differentiation of naive B cells (nBs) to antibody-secreting cells (ASCs). This process requires substantial epigenetic and transcriptional rewiring to ultimately repress the nB program and replace it with one conducive to ASC physiology and function. Notably, these reprogramming events occur within the framework of cell division. Efforts to understand the relationship of cell division with reprogramming and ASC differentiation in vivo have uncovered the timing and scope of reprogramming, as well as key factors that influence these events. Herein, we discuss the unique physiology of ASC and how nBs undergo epigenetic and genome architectural reorganization to acquire the necessary functions to support antibody production. We also discuss the stage-wise manner in which reprogramming occurs across cell divisions and how key molecular determinants can influence B cell fate outcomes.
Collapse
Affiliation(s)
- Dillon G. Patterson
- Department of Microbiology and Immunology, Emory University, Atlanta GA 30322
| | - Anna K. Kania
- Department of Microbiology and Immunology, Emory University, Atlanta GA 30322
| | - Zhihong Zuo
- Department of Microbiology and Immunology, Emory University, Atlanta GA 30322
- Xiangya School of Medicine, Central South University, Changsha, 410008, China
| | | | - Jeremy M. Boss
- Department of Microbiology and Immunology, Emory University, Atlanta GA 30322
| |
Collapse
|
|
14
|
Gaudette BT, Allman D. Biochemical coordination of plasma cell genesis. Immunol Rev 2021; 303:52-61. [PMID: 34313339 DOI: 10.1111/imr.12992] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 04/29/2021] [Indexed: 12/24/2022]
Abstract
Antibody-secreting plasma cells are a central component of short- and long-term adaptive immunity. Yet, many fundamental questions about how activated B cells decide to yield functional plasma cells have yet to be answered. Likewise, the biochemical processes underpinning the ability of plasma cells to generate and secrete large numbers of antibodies, the capacity of some plasma cell to sustain antibody secretion, presumably without interruption, for decades, and the capacity of long-lived plasma cells to avoid apoptosis despite the high-energy demands associated with sustained robust antibody synthesis and secretion each remain mysterious processes. Our objective here is to review what is currently known about these processes with an emphasis on the earliest phases of plasma cell genesis. Along the way, we will work toward developing a model that ties the biochemistry of plasma cell function and survival. The chief idea imbedded in this model is that progress toward understanding plasma cell survival mechanisms may require increased focus on the unique cell autonomous processes inherent in plasma cell differentiation and function.
Collapse
Affiliation(s)
- Brian T Gaudette
- The Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - David Allman
- The Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| |
Collapse
|
|
15
|
Trezise S, Nutt SL. The gene regulatory network controlling plasma cell function. Immunol Rev 2021; 303:23-34. [PMID: 34109653 DOI: 10.1111/imr.12988] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/13/2021] [Accepted: 05/14/2021] [Indexed: 12/16/2022]
Abstract
Antibodies are an essential element of the immune response to infection, and in long-term protection upon re-exposure to the same micro-organism. Antibodies are produced by plasmablasts and plasma cells, the terminally differentiated cells of the B lymphocyte lineage. These relatively rare populations, collectively termed antibody secreting cells (ASCs), have developed highly specialized transcriptional and metabolic pathways to facilitate their extraordinarily high rates of antibody synthesis and secretion. In this review, we discuss the gene regulatory network that controls ASC identity and function, with a particular focus on the processes that influence the transcription, translation, folding, modification and secretion of antibodies. We will address how ASCs have adapted their transcriptional, metabolic and protein homeostasis pathways to sustain such high rates of antibody production, and the roles that the major ASC regulators, the transcription factors, Irf4, Blimp-1 and Xbp1, play in co-ordinating these processes.
Collapse
Affiliation(s)
- Stephanie Trezise
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Stephen L Nutt
- The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.,Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| |
Collapse
|
|
16
|
Lemarié M, Chatonnet F, Caron G, Fest T. Early Emergence of Adaptive Mechanisms Sustaining Ig Production: Application to Antibody Therapy. Front Immunol 2021; 12:671998. [PMID: 33995412 PMCID: PMC8117215 DOI: 10.3389/fimmu.2021.671998] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Accepted: 04/12/2021] [Indexed: 01/13/2023] Open
Abstract
Antibody therapy, where artificially-produced immunoglobulins (Ig) are used to treat pathological conditions such as auto-immune diseases and cancers, is a very innovative and competitive field. Although substantial efforts have been made in recent years to obtain specific and efficient antibodies, there is still room for improvement especially when considering a precise tissular targeting or increasing antigen affinity. A better understanding of the cellular and molecular steps of terminal B cell differentiation, in which an antigen-activated B cell becomes an antibody secreting cell, may improve antibody therapy. In this review, we use our recently published data about human B cell differentiation, to show that the mechanisms necessary to adapt a metamorphosing B cell to its new secretory function appear quite early in the differentiation process i.e., at the pre-plasmablast stage. After characterizing the molecular pathways appearing at this stage, we will focus on recent findings about two main processes involved in antibody production: unfolded protein response (UPR) and endoplasmic reticulum (ER) stress. We’ll show that many genes coding for factors involved in UPR and ER stress are induced at the pre-plasmablast stage, sustaining our hypothesis. Finally, we propose to use this recently acquired knowledge to improve productivity of industrialized therapeutic antibodies.
Collapse
Affiliation(s)
- Maud Lemarié
- Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, UMR_S1236, Rennes, France
| | - Fabrice Chatonnet
- Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, UMR_S1236, Rennes, France.,Laboratoire d'Hématologie, Pôle de Biologie, Centre Hospitalier Universitaire, Rennes, France
| | - Gersende Caron
- Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, UMR_S1236, Rennes, France.,Laboratoire d'Hématologie, Pôle de Biologie, Centre Hospitalier Universitaire, Rennes, France
| | - Thierry Fest
- Université de Rennes 1, INSERM, Établissement Français du Sang de Bretagne, UMR_S1236, Rennes, France.,Laboratoire d'Hématologie, Pôle de Biologie, Centre Hospitalier Universitaire, Rennes, France
| |
Collapse
|
|
17
|
Wang P, Han L, Yu M, Cao Z, Li X, Shao Y, Zhu G. The Prognostic Value of PERK in Cancer and Its Relationship With Immune Cell Infiltration. Front Mol Biosci 2021; 8:648752. [PMID: 33937330 PMCID: PMC8085429 DOI: 10.3389/fmolb.2021.648752] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Accepted: 02/22/2021] [Indexed: 11/18/2022] Open
Abstract
Background: Protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is a type I transmembrane protein that functions as an endoplasmic reticulum (ER) stress sensor to regulate global protein synthesis. Recent research studies suggest that PERK, as an important receptor protein of unfolded protein response, is involved in the pathogenesis of many cancers. This study aimed to investigate PERK expression and its relationship with prognosis in pan-cancer and attempted to explore the relevant mechanism of PERK involved in the regulation of cancer pathogenesis. Methods: The Oncomine and TIMER databases were used to analyze the expression of PERK between pan-cancer samples and normal samples. Survival analysis was performed using the PrognoScan, Kaplan–Meier (K-M) plotter, and UALCAN databases. Gene set enrichment analysis (GSEA) was used to perform the functional enrichment analysis of the PERK gene in breast invasive carcinoma (BRCA), head and neck squamous cell carcinoma (HNSC), and thyroid carcinoma (THCA). The TIMER database was used to investigate the correlation between PERK expression and tumor-infiltrating immune cells and analyze the relationship of PERK with marker genes of immune cells which were downloaded from the CellMarker database in BRCA, HNSC, and THCA. Results: PERK was differentially expressed in various cancers, such as breast cancer, liver cancer, lung cancer, gastric carcinoma, lymphoma, thyroid cancer, leukemia, and head and neck squamous cell carcinomas. The high expression of PERK was associated with a poor prognosis in KIRP, LGG, BRCA, and THCA and with a favorable prognosis in HNSC. The results of GSEA indicated that PERK was mainly enriched in immune-related signaling pathways in BRCA, HNSC, and THCA. Moreover, PERK expression was significant positively correlated with infiltrating levels of macrophages and dendritic cells and was strongly associated with a variety of immune markers, especially macrophage mannose receptor 1 (MRC1, also called CD206) and T-helper cells (Th). Conclusion: The high expression of PERK could promote the infiltration of multiple immune cells in the tumor microenvironment and could deteriorate the outcomes of patients with breast and thyroid cancers, suggesting that PERK as well as tumor-infiltrating immune cells could be taken as potential biomarkers of prognosis.
Collapse
Affiliation(s)
- Peng Wang
- Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases, Key Laboratory of Biomedicine in Gene Diseases, Health of Anhui Higher Education Institutes, Anhui Normal University, Wuhu, China
| | - Liying Han
- Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases, Key Laboratory of Biomedicine in Gene Diseases, Health of Anhui Higher Education Institutes, Anhui Normal University, Wuhu, China
| | - Moxin Yu
- Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases, Key Laboratory of Biomedicine in Gene Diseases, Health of Anhui Higher Education Institutes, Anhui Normal University, Wuhu, China
| | - Zhengyu Cao
- Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases, Key Laboratory of Biomedicine in Gene Diseases, Health of Anhui Higher Education Institutes, Anhui Normal University, Wuhu, China
| | - Xiaoning Li
- Department of Clinical Laboratory, Yijishan Hospital of Wannan Medical College, Wuhu, China
| | - Yunxia Shao
- Department of Nephrology, Wuhu Hospital Affiliated to East China Normal University, Wuhu, China
| | - Guoping Zhu
- Anhui Provincial Key Laboratory of Molecular Enzymology and Mechanism of Major Diseases, Key Laboratory of Biomedicine in Gene Diseases, Health of Anhui Higher Education Institutes, Anhui Normal University, Wuhu, China
| |
Collapse
|
|
18
|
Xiong S, Chng WJ, Zhou J. Crosstalk between endoplasmic reticulum stress and oxidative stress: a dynamic duo in multiple myeloma. Cell Mol Life Sci 2021; 78:3883-3906. [PMID: 33599798 PMCID: PMC8106603 DOI: 10.1007/s00018-021-03756-3] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2020] [Revised: 12/19/2020] [Accepted: 01/05/2021] [Indexed: 02/07/2023]
Abstract
Under physiological and pathological conditions, cells activate the unfolded protein response (UPR) to deal with the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum. Multiple myeloma (MM) is a hematological malignancy arising from immunoglobulin-secreting plasma cells. MM cells are subject to continual ER stress and highly dependent on the UPR signaling activation due to overproduction of paraproteins. Mounting evidence suggests the close linkage between ER stress and oxidative stress, demonstrated by overlapping signaling pathways and inter-organelle communication pivotal to cell fate decision. Imbalance of intracellular homeostasis can lead to deranged control of cellular functions and engage apoptosis due to mutual activation between ER stress and reactive oxygen species generation through a self-perpetuating cycle. Here, we present accumulating evidence showing the interactive roles of redox homeostasis and proteostasis in MM pathogenesis and drug resistance, which would be helpful in elucidating the still underdefined molecular pathways linking ER stress and oxidative stress in MM. Lastly, we highlight future research directions in the development of anti-myeloma therapy, focusing particularly on targeting redox signaling and ER stress responses.
Collapse
Affiliation(s)
- Sinan Xiong
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Republic of Singapore
| | - Wee-Joo Chng
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Republic of Singapore.
- Centre for Translational Medicine, Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Republic of Singapore.
- Department of Hematology-Oncology, National University Cancer Institute of Singapore (NCIS), The National University Health System (NUHS), 1E, Kent Ridge Road, Singapore, 119228, Republic of Singapore.
| | - Jianbiao Zhou
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117597, Republic of Singapore.
- Centre for Translational Medicine, Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Republic of Singapore.
| |
Collapse
|
|
19
|
Delgado-Benito V, Berruezo-Llacuna M, Altwasser R, Winkler W, Sundaravinayagam D, Balasubramanian S, Caganova M, Graf R, Rahjouei A, Henke MT, Driesner M, Keller L, Prigione A, Janz M, Akalin A, Di Virgilio M. PDGFA-associated protein 1 protects mature B lymphocytes from stress-induced cell death and promotes antibody gene diversification. J Exp Med 2021; 217:151913. [PMID: 32609329 PMCID: PMC7537392 DOI: 10.1084/jem.20200137] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 04/20/2020] [Accepted: 05/19/2020] [Indexed: 12/13/2022] Open
Abstract
The establishment of protective humoral immunity is dependent on the ability of mature B cells to undergo antibody gene diversification while adjusting to the physiological stressors induced by activation with the antigen. Mature B cells diversify their antibody genes by class switch recombination (CSR) and somatic hypermutation (SHM), which are both dependent on efficient induction of activation-induced cytidine deaminase (AID). Here, we identified PDGFA-associated protein 1 (Pdap1) as an essential regulator of cellular homeostasis in mature B cells. Pdap1 deficiency leads to sustained expression of the integrated stress response (ISR) effector activating transcription factor 4 (Atf4) and induction of the ISR transcriptional program, increased cell death, and defective AID expression. As a consequence, loss of Pdap1 reduces germinal center B cell formation and impairs CSR and SHM. Thus, Pdap1 protects mature B cells against chronic ISR activation and ensures efficient antibody diversification by promoting their survival and optimal function.
Collapse
Affiliation(s)
- Verónica Delgado-Benito
- Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Maria Berruezo-Llacuna
- Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Robert Altwasser
- Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.,Bioinformatics and Omics Data Science Technology Platform, Berlin Institute of Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Wiebke Winkler
- Laboratory of Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.,Laboratory of Biology of Malignant Lymphomas, Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité, University Medicine, Berlin, Germany
| | - Devakumar Sundaravinayagam
- Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Sandhya Balasubramanian
- Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Marieta Caganova
- Laboratory of Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Robin Graf
- Laboratory of Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Ali Rahjouei
- Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Marie-Thérèse Henke
- Laboratory of Mitochondria and Cell Fate Reprogramming, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Madlen Driesner
- Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Lisa Keller
- Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Alessandro Prigione
- Laboratory of Mitochondria and Cell Fate Reprogramming, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.,Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich Heine University, Düsseldorf, Germany
| | - Martin Janz
- Laboratory of Biology of Malignant Lymphomas, Experimental and Clinical Research Center, Max Delbrück Center for Molecular Medicine in the Helmholtz Association and Charité, University Medicine, Berlin, Germany
| | - Altuna Akalin
- Bioinformatics and Omics Data Science Technology Platform, Berlin Institute of Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Michela Di Virgilio
- Laboratory of Genome Diversification and Integrity, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany.,Charité-Universitätsmedizin Berlin, Berlin, Germany
| |
Collapse
|
|
20
|
van Anken E, Bakunts A, Hu CCA, Janssens S, Sitia R. Molecular Evaluation of Endoplasmic Reticulum Homeostasis Meets Humoral Immunity. Trends Cell Biol 2021; 31:529-541. [PMID: 33685797 DOI: 10.1016/j.tcb.2021.02.004] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2020] [Revised: 02/02/2021] [Accepted: 02/03/2021] [Indexed: 12/16/2022]
Abstract
The biosynthesis of about one third of the human proteome, including membrane receptors and secreted proteins, occurs in the endoplasmic reticulum (ER). Conditions that perturb ER homeostasis activate the unfolded protein response (UPR). An 'optimistic' UPR output aims at restoring homeostasis by reinforcement of machineries that guarantee efficiency and fidelity of protein biogenesis in the ER. Yet, once the UPR 'deems' that ER homeostatic readjustment fails, it transitions to a 'pessimistic' output, which, depending on the cell type, will result in apoptosis. In this article, we discuss emerging concepts on how the UPR 'evaluates' ER stress, how the UPR is repurposed, in particular in B cells, and how UPR-driven counter-selection of cells undergoing homeostatic failure serves organismal homeostasis and humoral immunity.
Collapse
Affiliation(s)
- Eelco van Anken
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
| | - Anush Bakunts
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy
| | | | - Sophie Janssens
- Laboratory for Endoplasmic Reticulum (ER) Stress and Inflammation, VIB Center for Inflammation Research, and Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
| | - Roberto Sitia
- Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| |
Collapse
|
|
21
|
Ripperger TJ, Bhattacharya D. Transcriptional and Metabolic Control of Memory B Cells and Plasma Cells. Annu Rev Immunol 2021; 39:345-368. [PMID: 33556247 DOI: 10.1146/annurev-immunol-093019-125603] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
For many infections and almost all vaccines, neutralizing-antibody-mediated immunity is the primary basis and best functional correlate of immunological protection. Durable long-term humoral immunity is mediated by antibodies secreted by plasma cells that preexist subsequent exposures and by memory B cells that rapidly respond to infections once they have occurred. In the midst of the current pandemic of coronavirus disease 2019, it is important to define our current understanding of the unique roles of memory B cells and plasma cells in immunity and the factors that control the formation and persistence of these cell types. This fundamental knowledge is the basis to interpret findings from natural infections and vaccines. Here, we review transcriptional and metabolic programs that promote and support B cell fates and functions, suggesting points at which these pathways do and do not intersect.
Collapse
Affiliation(s)
- Tyler J Ripperger
- Department of Immunobiology, University of Arizona College of Medicine-Tucson, Tucson, Arizona 85724, USA; ,
| | - Deepta Bhattacharya
- Department of Immunobiology, University of Arizona College of Medicine-Tucson, Tucson, Arizona 85724, USA; ,
| |
Collapse
|
|
22
|
Cocco M, Care MA, Saadi A, Al-Maskari M, Doody G, Tooze R. A dichotomy of gene regulatory associations during the activated B-cell to plasmablast transition. Life Sci Alliance 2020; 3:e202000654. [PMID: 32843533 PMCID: PMC7471511 DOI: 10.26508/lsa.202000654] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Revised: 08/12/2020] [Accepted: 08/12/2020] [Indexed: 01/22/2023] Open
Abstract
The activated B-cell (ABC) to plasmablast transition encompasses the cusp of antibody-secreting cell (ASC) differentiation. We explore this transition with integrated analysis in human cells, focusing on changes that follow removal from CD40-mediated signals. Within hours of input signal loss, cell growth programs shift toward enhanced proliferation, accompanied by ER-stress response, and up-regulation of ASC features. Clustering of genomic occupancy for IRF4, BLIMP1, XBP1, and CTCF with histone marks identifies a dichotomy: XBP1 and IRF4 link to induced but not repressed gene modules in plasmablasts, whereas BLIMP1 links to modules of ABC genes that are repressed, but not to activated genes. Between ABC and plasmablast states, IRF4 shifts away from AP1/IRF composite elements while maintaining occupancy at IRF and ETS/IRF elements. This parallels the loss of BATF expression, which is identified as a potential BLIMP1 target. In plasmablasts, IRF4 acquires an association with CTCF, a feature maintained in plasma cell myeloma lines. Thus, shifting occupancy links IRF4 to both ABC and ASC gene expression, whereas BLIMP1 occupancy links to repression of the activation state.
Collapse
Affiliation(s)
- Mario Cocco
- Division of Immunology and Haematology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Matthew A Care
- Division of Immunology and Haematology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
- Bioinformatics Group, Institute of Molecular and Cellular Biology, University of Leeds, Leeds, UK
| | - Amel Saadi
- Division of Immunology and Haematology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Muna Al-Maskari
- Division of Immunology and Haematology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
- Department of Medicine, Sultan Qaboos University Hospital, Muscat, Oman
| | - Gina Doody
- Division of Immunology and Haematology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| | - Reuben Tooze
- Division of Immunology and Haematology, Leeds Institute of Medical Research, University of Leeds, Leeds, UK
| |
Collapse
|
|
23
|
Metcalf MG, Higuchi-Sanabria R, Garcia G, Tsui CK, Dillin A. Beyond the cell factory: Homeostatic regulation of and by the UPR ER. SCIENCE ADVANCES 2020; 6:eabb9614. [PMID: 32832649 PMCID: PMC7439504 DOI: 10.1126/sciadv.abb9614] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Accepted: 06/02/2020] [Indexed: 05/02/2023]
Abstract
The endoplasmic reticulum (ER) is commonly referred to as the factory of the cell, as it is responsible for a large amount of protein and lipid synthesis. As a membrane-bound organelle, the ER has a distinct environment that is ideal for its functions in synthesizing these primary cellular components. Many different quality control machineries exist to maintain ER stability under the stresses associated with synthesizing, folding, and modifying complex proteins and lipids. The best understood of these mechanisms is the unfolded protein response of the ER (UPRER), in which transmembrane proteins serve as sensors, which trigger a coordinated transcriptional response of genes dedicated for mitigating the stress. As the name suggests, the UPRER is most well described as a functional response to protein misfolding stress. Here, we focus on recent findings and emerging themes in additional roles of the UPRER outside of protein homeostasis, including lipid homeostasis, autophagy, apoptosis, and immunity.
Collapse
|
|
24
|
Abstract
Antibody-secreting plasma cells are the central pillars of humoral immunity. They are generated in a fundamental cellular restructuring process from naive B cells upon contact with antigen. This outstanding process is guided and controlled by a complex transcriptional network accompanied by a fascinating morphological metamorphosis, governed by the combined action of Blimp-1, Xbp-1 and IRF-4. The survival of plasma cells requires the intimate interaction with a specific microenvironment, consisting of stromal cells and cells of hematopoietic origin. Cell-cell contacts, cytokines and availability of metabolites such as glucose and amino acids modulate the survival abilities of plasma cells in their niches. Moreover, plasma cells have been shown to regulate immune responses by releasing cytokines. Furthermore, plasma cells are central players in autoimmune diseases and malignant transformation of plasma cells can result in the generation of multiple myeloma. Hence, the development of sophisticated strategies to deplete autoreactive plasma cells and myeloma cells represents a challenge for current and future research.
Collapse
Affiliation(s)
- Wolfgang Schuh
- Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger Center, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany.
| | - Dirk Mielenz
- Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger Center, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| | - Hans-Martin Jäck
- Division of Molecular Immunology, Department of Internal Medicine III, Nikolaus-Fiebiger Center, University Hospital Erlangen, Friedrich-Alexander-University of Erlangen-Nürnberg, Erlangen, Germany
| |
Collapse
|
|
25
|
Wang V, Davis DA, Deleage C, Brands C, Choi HS, Haque M, Yarchoan R. Induction of Kaposi's Sarcoma-Associated Herpesvirus-Encoded Thymidine Kinase (ORF21) by X-Box Binding Protein 1. J Virol 2020; 94:e01555-19. [PMID: 31801863 PMCID: PMC7022350 DOI: 10.1128/jvi.01555-19] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 11/26/2019] [Indexed: 12/11/2022] Open
Abstract
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). Like other herpesviruses, it has latent and lytic repertoires. However, there is evidence that some lytic genes can be directly activated by certain cellular factors. Cells undergoing endoplasmic reticulum stress express spliced X-box binding protein 1 (XBP-1s). XBP-1s is also present in large amounts in germinal center B cells. XBP-1s can activate the KSHV replication and transcription activator (RTA) and lytic replication. It can also directly activate KSHV-encoded viral interleukin-6 (vIL-6) and, thus, contribute to the pathogenesis of KSHV MCD. KSHV thymidine kinase (TK), the ORF21 gene product, can enhance the production of dTTP and is important for lytic replication. It can also phosphorylate zidovudine and ganciclovir to toxic moieties, enabling treatment of KSHV-MCD with these drugs. We show here that XBP-1s can directly activate ORF21 and that this activation is mediated primarily through two XBP-response elements (XRE) on the ORF21 promoter region. Deletion or mutation of these elements eliminated XBP-1s-induced upregulation of the promoter, and chromatin immunoprecipitation studies provide evidence that XBP-1s can bind to both XREs. Exposure of PEL cells to a chemical inducer of XBP-1s can induce ORF21 within 4 hours, and ORF21 expression in the lymph nodes of patients with KSHV-MCD is predominantly found in cells with XBP-1. Thus, XBP-1s may directly upregulate KSHV ORF21 and, thus, contribute to the pathogenesis of KSHV-MCD and the activity of zidovudine and valganciclovir in this disease.IMPORTANCE Spliced X-box binding protein 1 (XBP-1s), part of the unfolded protein response and expressed in developing germinal center B cells, can induce Kaposi's sarcoma-associated herpesvirus (KSHV) lytic replication and directly activate viral interleukin-6 (vIL-6). We show here that XBP-1s can also directly activate KSHV ORF21, a lytic gene. ORF21 encodes KSHV thymidine kinase (TK), which increases the pool of dTTP for viral replication and enhances lytic replication. Direct activation of ORF21 by XBP-1s can enhance viral replication in germinal center B cells and contribute to the pathogenesis of KSHV multicentric Castleman disease (MCD). KSHV-MCD is characterized by systemic inflammation caused, in part, by lytic replication and overproduction of KSHV vIL-6 in XBP-1s-expressing lymph node plasmablasts. KSHV thymidine kinase can phosphorylate zidovudine and ganciclovir to toxic moieties, and direct activation of ORF21 by XBP-1s may also help explain the effectiveness of zidovudine and valganciclovir in the treatment of KSHV-MCD.
Collapse
Affiliation(s)
- Victoria Wang
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - David A Davis
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Claire Deleage
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Catherine Brands
- AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, Maryland, USA
| | - Hong S Choi
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Muzammel Haque
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Robert Yarchoan
- HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| |
Collapse
|
|
26
|
Li A, Song NJ, Riesenberg BP, Li Z. The Emerging Roles of Endoplasmic Reticulum Stress in Balancing Immunity and Tolerance in Health and Diseases: Mechanisms and Opportunities. Front Immunol 2020; 10:3154. [PMID: 32117210 PMCID: PMC7026265 DOI: 10.3389/fimmu.2019.03154] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 12/30/2019] [Indexed: 12/14/2022] Open
Abstract
The endoplasmic reticulum (ER) is an organelle equipped with mechanisms for proper protein folding, trafficking, and degradation to maintain protein homeostasis in the secretory pathway. As a defense mechanism, perturbation of ER proteostasis by ER stress agents activates a cascade of signaling pathways from the ER to the nucleus known as unfolded protein response (UPR). The primary goal of UPR is to induce transcriptional and translational programs to restore ER homeostasis for cell survival. As such, defects in UPR signaling have been implicated as a key contributor to multiple diseases including metabolic diseases, degenerative diseases, inflammatory disorders, and cancer. Growing evidence support the critical role of ER stress in regulating the fate as well as the magnitude of the immune response. Moreover, the availability of multiple UPR pharmacological inhibitors raises the hope that targeting UPR can be a new strategy for immune modulation and immunotherapy of diseases. This paper reviews the principal mechanisms by which ER stress affects immune cell biology and function, with a focus of discussion on UPR-associated immunopathology and the development of potential ER stress-targeted therapeutics.
Collapse
Affiliation(s)
- Anqi Li
- College of Medicine, The Ohio State University, Columbus, OH, United States.,The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, United States
| | - No-Joon Song
- The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, United States
| | - Brian P Riesenberg
- The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, United States
| | - Zihai Li
- College of Medicine, The Ohio State University, Columbus, OH, United States.,The James Comprehensive Cancer Center, Pelotonia Institute for Immuno-Oncology, The Ohio State University, Columbus, OH, United States.,Division of Medical Oncology, Department of Medicine, The Ohio State University, Columbus, OH, United States
| |
Collapse
|
|
27
|
D'Souza L, Bhattacharya D. Plasma cells: You are what you eat. Immunol Rev 2019; 288:161-177. [PMID: 30874356 DOI: 10.1111/imr.12732] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Accepted: 12/03/2018] [Indexed: 12/26/2022]
Abstract
Plasma cells are terminally differentiated B lymphocytes that constitutively secrete antibodies. These antibodies can provide protection against pathogens, and their quantity and quality are the best clinical correlates of vaccine efficacy. As such, plasma cell lifespan is the primary determinant of the duration of humoral immunity. Yet dysregulation of plasma cell function can cause autoimmunity or multiple myeloma. The longevity of plasma cells is primarily dictated by nutrient uptake and non-transcriptionally regulated metabolic pathways. We have previously shown a positive effect of glucose uptake and catabolism on plasma cell longevity and function. In this review, we discuss these findings with an emphasis on nutrient uptake and its effects on respiratory capacity, lifespan, endoplasmic reticulum stress, and antibody secretion in plasma cells. We further discuss how some of these pathways may be dysregulated in multiple myeloma, potentially providing new therapeutic targets. Finally, we speculate on the connection between plasma cell intrinsic metabolism and systemic changes in nutrient availability and metabolic diseases.
Collapse
Affiliation(s)
- Lucas D'Souza
- Department of Immunobiology, University of Arizona College of Medicine, Tucson, Arizona
| | - Deepta Bhattacharya
- Department of Immunobiology, University of Arizona College of Medicine, Tucson, Arizona
| |
Collapse
|
|
28
|
Gerakis Y, Quintero M, Li H, Hetz C. The UFMylation System in Proteostasis and Beyond. Trends Cell Biol 2019; 29:974-986. [PMID: 31703843 PMCID: PMC6917045 DOI: 10.1016/j.tcb.2019.09.005] [Citation(s) in RCA: 114] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Revised: 09/24/2019] [Accepted: 09/25/2019] [Indexed: 12/16/2022]
Abstract
Post-translational modifications are at the apex of cellular communication and eventually regulate every aspect of life. The identification of new post-translational modifiers is opening alternative avenues in understanding fundamental cell biology processes and may ultimately provide novel therapeutic opportunities. The ubiquitin-fold modifier 1 (UFM1) is a post-translational modifier discovered a decade ago but its biological significance has remained mostly unknown. The field has recently witnessed an explosion of research uncovering the implications of the pathway to cellular homeostasis in living organisms. We overview recent advances in the function and regulation of the UFM1 pathway, and its implications for cell physiology and disease.
Collapse
Affiliation(s)
- Yannis Gerakis
- Biomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile, Santiago, Chile; FONDAP (Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias) Center for Geroscience (GERO), Brain Health and Metabolism, Santiago, Chile; Buck Institute for Research on Aging, Novato, CA 94945, USA
| | - Michaela Quintero
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
| | - Honglin Li
- Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA.
| | - Claudio Hetz
- Biomedical Neuroscience Institute (BNI), Faculty of Medicine, University of Chile, Santiago, Chile; FONDAP (Fondo de Financiamiento de Centros de Investigación en Áreas Prioritarias) Center for Geroscience (GERO), Brain Health and Metabolism, Santiago, Chile; Buck Institute for Research on Aging, Novato, CA 94945, USA; Cellular and Molecular Biology Program, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
| |
Collapse
|
|
29
|
Naughton M, McMahon J, Healy S, FitzGerald U. Profile of the unfolded protein response in rat cerebellar cortical development. J Comp Neurol 2019; 527:2910-2924. [PMID: 31132146 DOI: 10.1002/cne.24718] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Revised: 04/01/2019] [Accepted: 05/16/2019] [Indexed: 12/13/2022]
Abstract
The unfolded protein response (UPR) has been reported during normal development of cortical neurons and cerebellar white matter and may also contribute to the pathogenesis of neurological conditions, such as Marinesco-Sjogren syndrome and Borna virus infection, which result in cerebellar defects. The UPR is initiated when the processing capacity of the endoplasmic reticulum (ER) is overwhelmed. Misfolded proteins accumulate and can activate ER stress sensors; PKR-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), activated transcription factor 6 (ATF6) and their downstream targets glucose-regulated protein 78 (GRP78), glucose-regulated protein 94 (GRP94) and protein disulfide isomerase (PDI). In order to provide a fuller appreciation of the possible importance of ER stress-associated proteins in the context of cerebellar disease, we have profiled the expression of ER stress sensors and their downstream targets in the developing cerebellar cortex in postnatal rat. Activation of PERK and IRE1 stress sensors was observed for the first time in normally developing granule cell precursors. A second proliferative pPERK-positive population was also detected in the internal granular layer (IGL). In general, the density of UPR protein-positive cells was found to decrease significantly when profiles in early and late postnatal ages were compared. These data may be relevant to studies of medulloblastoma and warrant further investigation.
Collapse
Affiliation(s)
- Michelle Naughton
- Galway Neuroscience Centre, School of Natural Sciences, National University of Ireland, Galway, Ireland
| | - Jill McMahon
- Galway Neuroscience Centre, School of Natural Sciences, National University of Ireland, Galway, Ireland
| | - Sinéad Healy
- Galway Neuroscience Centre, School of Natural Sciences, National University of Ireland, Galway, Ireland
| | - Una FitzGerald
- Galway Neuroscience Centre, School of Natural Sciences, National University of Ireland, Galway, Ireland
| |
Collapse
|
|
30
|
Zhu H, Bhatt B, Sivaprakasam S, Cai Y, Liu S, Kodeboyina SK, Patel N, Savage NM, Sharma A, Kaufman RJ, Li H, Singh N. Ufbp1 promotes plasma cell development and ER expansion by modulating distinct branches of UPR. Nat Commun 2019; 10:1084. [PMID: 30842412 PMCID: PMC6403283 DOI: 10.1038/s41467-019-08908-5] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Accepted: 01/24/2019] [Indexed: 02/03/2023] Open
Abstract
The IRE1α/XBP1 branch of unfolded protein response (UPR) pathway has a critical function in endoplasmic reticulum (ER) expansion in plasma cells via unknown mechanisms; interestingly, another UPR branch, PERK, is suppressed during plasma cell development. Here we show that Ufbp1, a target and cofactor of the ufmylation pathway, promotes plasma cell development by suppressing the activation of PERK. By contrast, the IRE1α/XBP1 axis upregulates the expression of Ufbp1 and ufmylation pathway genes in plasma cells, while Ufbp1 deficiency impairs ER expansion in plasma cells and retards immunoglobulin production. Structure and function analysis suggests that lysine 267 of Ufbp1, the main lysine in Ufbp1 that undergoes ufmylation, is dispensable for the development of plasmablasts, but is required for immunoglobulin production and stimulation of ER expansion in IRE1α-deficient plasmablasts. Thus, Ufbp1 distinctly regulates different branches of UPR pathway to promote plasma cell development and function.
Collapse
Affiliation(s)
- Huabin Zhu
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, 30912, USA
| | - Brinda Bhatt
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, 30912, USA
| | - Sathish Sivaprakasam
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, 30912, USA
- Department of Cell Biology and Biochemistry, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA
| | - Yafei Cai
- College of Animal Science and Technology, Nanjing Agricultural University, 1 Weigang, Nanjing, 210095, Jiangsu Province, China
| | - Siyang Liu
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, 30912, USA
| | - Sai Karthik Kodeboyina
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, 30912, USA
| | - Nikhil Patel
- Department of Pathology, Augusta University, Augusta, GA, 30912, USA
| | - Natasha M Savage
- Department of Pathology, Augusta University, Augusta, GA, 30912, USA
| | - Ashok Sharma
- Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, 30912, USA
| | - Randal J Kaufman
- Degenerative Diseases Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, 92307, USA
| | - Honglin Li
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, 30912, USA
- Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA
| | - Nagendra Singh
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, 30912, USA.
- Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA.
| |
Collapse
|
|
31
|
Carew NT, Nelson AM, Liang Z, Smith SM, Milcarek C. Linking Endoplasmic Reticular Stress and Alternative Splicing. Int J Mol Sci 2018; 19:ijms19123919. [PMID: 30544499 PMCID: PMC6321306 DOI: 10.3390/ijms19123919] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 12/04/2018] [Accepted: 12/05/2018] [Indexed: 12/16/2022] Open
Abstract
RNA splicing patterns in antibody-secreting cells are shaped by endoplasmic reticulum stress, ELL2 (eleven-nineteen lysine-rich leukemia gene 2) induction, and changes in the levels of snRNAs. Endoplasmic reticulum stress induces the unfolded protein response comprising a highly conserved set of genes crucial for cell survival; among these is Ire1, whose auto-phosphorylation drives it to acquire a regulated mRNA decay activity. The mRNA-modifying function of phosphorylated Ire1 non-canonically splices Xbp1 mRNA and yet degrades other cellular mRNAs with related motifs. Naïve splenic B cells will activate Ire1 phosphorylation early on after lipopolysaccharide (LPS) stimulation, within 18 h; large-scale changes in mRNA content and splicing patterns result. Inhibition of the mRNA-degradation function of Ire1 is correlated with further differences in the splicing patterns and a reduction in the mRNA factors for snRNA transcription. Some of the >4000 splicing changes seen at 18 h after LPS stimulation persist into the late stages of antibody secretion, up to 72 h. Meanwhile some early splicing changes are supplanted by new splicing changes introduced by the up-regulation of ELL2, a transcription elongation factor. ELL2 is necessary for immunoglobulin secretion and does this by changing mRNA processing patterns of immunoglobulin heavy chain and >5000 other genes.
Collapse
Affiliation(s)
- Nolan T Carew
- School of Medicine, Department of Immunology, University of Pittsburgh, E1059 Biomedical Science Tower, Pittsburgh, PA 15261, USA.
| | - Ashley M Nelson
- School of Medicine, Department of Immunology, University of Pittsburgh, E1059 Biomedical Science Tower, Pittsburgh, PA 15261, USA.
| | - Zhitao Liang
- School of Medicine, Department of Immunology, University of Pittsburgh, E1059 Biomedical Science Tower, Pittsburgh, PA 15261, USA.
| | - Sage M Smith
- School of Medicine, Department of Immunology, University of Pittsburgh, E1059 Biomedical Science Tower, Pittsburgh, PA 15261, USA.
| | - Christine Milcarek
- School of Medicine, Department of Immunology, University of Pittsburgh, E1059 Biomedical Science Tower, Pittsburgh, PA 15261, USA.
| |
Collapse
|
|
32
|
García-González P, Cabral-Miranda F, Hetz C, Osorio F. Interplay Between the Unfolded Protein Response and Immune Function in the Development of Neurodegenerative Diseases. Front Immunol 2018; 9:2541. [PMID: 30450103 PMCID: PMC6224445 DOI: 10.3389/fimmu.2018.02541] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Accepted: 10/15/2018] [Indexed: 12/25/2022] Open
Abstract
Emerging evidence suggests that the immune and nervous systems are in close interaction in health and disease conditions. Protein aggregation and proteostasis dysfunction at the level of the endoplasmic reticulum (ER) are central contributors to neurodegenerative diseases. The unfolded protein response (UPR) is the main transduction pathway that maintains protein homeostasis under conditions of protein misfolding and aggregation. Brain inflammation often coexists with the degenerative process in different brain diseases. Interestingly, besides its well-described role in neuronal fitness, the UPR has also emerged as a key regulator of ontogeny and function of several immune cell types. Nevertheless, the contribution of the UPR to brain inflammation initiated by immune cells remains largely unexplored. In this review, we provide a perspective on the potential role of ER stress signaling in brain-associated immune cells and the possible implications to neuroinflammation and development of neurodegenerative diseases.
Collapse
Affiliation(s)
- Paulina García-González
- Laboratory of Immunology and Cellular Stress, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| | - Felipe Cabral-Miranda
- Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.,Brain Health and Metabolism, FONDAP Center for Geroscience, Santiago, Chile.,Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.,Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Claudio Hetz
- Faculty of Medicine, Biomedical Neuroscience Institute, University of Chile, Santiago, Chile.,Brain Health and Metabolism, FONDAP Center for Geroscience, Santiago, Chile.,Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.,Buck Institute for Research on Aging, Novato, CA, United States.,Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA, United States
| | - Fabiola Osorio
- Laboratory of Immunology and Cellular Stress, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, University of Chile, Santiago, Chile
| |
Collapse
|
|
33
|
Al-Maskari M, Care MA, Robinson E, Cocco M, Tooze RM, Doody GM. Site-1 protease function is essential for the generation of antibody secreting cells and reprogramming for secretory activity. Sci Rep 2018; 8:14338. [PMID: 30254311 PMCID: PMC6156501 DOI: 10.1038/s41598-018-32705-7] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 09/11/2018] [Indexed: 01/08/2023] Open
Abstract
The unfolded protein response (UPR) and activation of XBP1 is necessary for high secretory efficiency and functional differentiation of antibody secreting cells (ASCs). The UPR additionally includes a branch in which membrane-bound transcription factors, exemplified by ATF6, undergo intramembrane-proteolysis by the sequential action of site-1 (MBTPS1/S1P) and site-2 proteases (MBTPS2/S2P) and release of the cytoplasmic domain as an active transcription factor. Such regulation is shared with a family of CREB3-related transcription factors and sterol regulatory element-binding proteins (SREBPs). Of these, we identify that the CREB3 family member CREB3L2 is strongly induced and activated during the transition from B-cell to plasma cell state. Inhibition of site-1 protease leads to a profound reduction in plasmablast number linked to induction of autophagy. Plasmablasts generated in the presence of site-1 protease inhibitor segregated into CD38high and CD38low populations, the latter characterized by a marked reduction in the capacity to secrete IgG. Site-1 protease inhibition is accompanied by a distinctive change in gene expression associated with amino acid, steroid and fatty acid synthesis pathways. These results demonstrate that transcriptional control of metabolic programs necessary for secretory activity can be targeted via site-1 protease inhibition during ASC differentiation.
Collapse
Affiliation(s)
- Muna Al-Maskari
- Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, United Kingdom
| | - Matthew A Care
- Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, United Kingdom
- Bioinformatics Group, School of Molecular and Cellular Biology, University of Leeds, Leeds, LS2 9JT, United Kingdom
| | - Emily Robinson
- Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, United Kingdom
| | - Mario Cocco
- Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, United Kingdom
| | - Reuben M Tooze
- Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, United Kingdom
| | - Gina M Doody
- Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, LS9 7TF, United Kingdom.
| |
Collapse
|
|
34
|
Lam WY, Jash A, Yao CH, D'Souza L, Wong R, Nunley RM, Meares GP, Patti GJ, Bhattacharya D. Metabolic and Transcriptional Modules Independently Diversify Plasma Cell Lifespan and Function. Cell Rep 2018; 24:2479-2492.e6. [PMID: 30157439 PMCID: PMC6172041 DOI: 10.1016/j.celrep.2018.07.084] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 06/15/2018] [Accepted: 07/25/2018] [Indexed: 01/12/2023] Open
Abstract
Plasma cell survival and the consequent duration of immunity vary widely with infection or vaccination. Using fluorescent glucose analog uptake, we defined multiple developmentally independent mouse plasma cell populations with varying lifespans. Long-lived plasma cells imported more fluorescent glucose analog, expressed higher surface levels of the amino acid transporter CD98, and had more autophagosome mass than did short-lived cells. Low amino acid concentrations triggered reductions in both antibody secretion and mitochondrial respiration, especially by short-lived plasma cells. To explain these observations, we found that glutamine was used for both mitochondrial respiration and anaplerotic reactions, yielding glutamate and aspartate for antibody synthesis. Endoplasmic reticulum (ER) stress responses, which link metabolism to transcriptional outcomes, were similar between long- and short-lived subsets. Accordingly, population and single-cell transcriptional comparisons across mouse and human plasma cell subsets revealed few consistent and conserved differences. Thus, plasma cell antibody secretion and lifespan are primarily defined by non-transcriptional metabolic traits.
Collapse
Affiliation(s)
- Wing Y Lam
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Arijita Jash
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Cong-Hui Yao
- Department of Chemistry, Washington University, St. Louis, MO 63110, USA
| | - Lucas D'Souza
- Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ 85724, USA
| | - Rachel Wong
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ 85724, USA
| | - Ryan M Nunley
- Washington University Orthopedics, Barnes Jewish Hospital, St. Louis, MO 63110, USA
| | - Gordon P Meares
- Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26505, USA
| | - Gary J Patti
- Department of Chemistry, Washington University, St. Louis, MO 63110, USA
| | - Deepta Bhattacharya
- Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ 85724, USA.
| |
Collapse
|
|
35
|
Redox-Dependent Circuits Regulating B Lymphocyte Physiology. Immunology 2018. [DOI: 10.1016/b978-0-12-809819-6.00013-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
|
|
36
|
Lam WY, Bhattacharya D. Metabolic Links between Plasma Cell Survival, Secretion, and Stress. Trends Immunol 2017; 39:19-27. [PMID: 28919256 DOI: 10.1016/j.it.2017.08.007] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2017] [Revised: 08/18/2017] [Accepted: 08/18/2017] [Indexed: 01/12/2023]
Abstract
Humoral immunity is generated and maintained by antigen-specific antibodies that counter infectious pathogens. Plasma cells are the major producers of antibodies during and after infections, and each plasma cell produces some thousands of antibody molecules per second. This magnitude of secretion requires enormous quantities of amino acids and glycosylation sugars to properly build and fold antibodies, biosynthetic substrates to fuel endoplasmic reticulum (ER) biogenesis, and additional carbon sources to generate energy. Many of these processes are likely to be linked, thereby affording possibilities to improve vaccine design and to develop new therapies for autoimmunity. We review here aspects of plasma cell biology with an emphasis on recent studies and the relationships between intermediary metabolism, antibody production, and lifespan.
Collapse
Affiliation(s)
- Wing Y Lam
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA
| | - Deepta Bhattacharya
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, MO 63110, USA; Current address: Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ 85724, USA.
| |
Collapse
|
|
37
|
Zhu YX, Shi CX, Bruins LA, Jedlowski P, Wang X, Kortüm KM, Luo M, Ahmann JM, Braggio E, Stewart AK. Loss of FAM46C Promotes Cell Survival in Myeloma. Cancer Res 2017; 77:4317-4327. [PMID: 28619709 DOI: 10.1158/0008-5472.can-16-3011] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2016] [Revised: 04/17/2017] [Accepted: 06/09/2017] [Indexed: 02/06/2023]
Abstract
FAM46C is one of the most recurrently mutated genes in multiple myeloma; however its role in disease pathogenesis has not been determined. Here we demonstrate that wild-type (WT) FAM46C overexpression induces substantial cytotoxicity in multiple myeloma cells. In contrast, FAM46C mutations found in multiple myeloma patients abrogate this cytotoxicity, indicating a survival advantage conferred by the FAM46C mutant phenotype. WT FAM46C overexpression downregulated IRF4, CEBPB, and MYC and upregulated immunoglobulin (Ig) light chain and HSPA5/BIP Furthermore, pathway analysis suggests that enforced FAM46C expression activated the unfolded protein response pathway and induced mitochondrial dysfunction. CRISPR-mediated depletion of endogenous FAM46C enhanced multiple myeloma cell growth, decreased Ig light chain and HSPA5/BIP expression, activated ERK and antiapoptotic signaling, and conferred relative resistance to dexamethasone and lenalidomide treatments. Genes altered in FAM46C-depleted cells were enriched for signaling pathways regulating estrogen, glucocorticoid, B-cell receptor signaling, and ATM signaling. Together these results implicate FAM46C in myeloma cell growth and survival and identify FAM46C mutation as a contributor to myeloma pathogenesis and disease progression via perturbation in plasma cell differentiation and endoplasmic reticulum homeostasis. Cancer Res; 77(16); 4317-27. ©2017 AACR.
Collapse
Affiliation(s)
- Yuan Xiao Zhu
- Division of Hematology, Mayo Clinic Scottsdale, Arizona
| | - Chang-Xin Shi
- Division of Hematology, Mayo Clinic Scottsdale, Arizona
| | | | | | - Xuewei Wang
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic Rochester, Minnesota
| | | | - Moulun Luo
- Center for Metabolic and Vascular Biology, Arizona State University, Tempe, Arizona
| | | | | | - A Keith Stewart
- Division of Hematology, Mayo Clinic Scottsdale, Arizona. .,Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota
| |
Collapse
|
|
38
|
Jeong M, Jang E, Choi SS, Ji C, Lee K, Youn J. The Function of FK506-Binding Protein 13 in Protein Quality Control Protects Plasma Cells from Endoplasmic Reticulum Stress-Associated Apoptosis. Front Immunol 2017; 8:222. [PMID: 28303141 PMCID: PMC5332356 DOI: 10.3389/fimmu.2017.00222] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Accepted: 02/16/2017] [Indexed: 12/23/2022] Open
Abstract
Plasma cells (PCs) are exposed to intense endoplasmic reticulum (ER) stress imposed by enormous rates of immunoglobulin (Ig) synthesis and secretion. Therefore, protein homeostasis is crucial for the survival of PCs, but its molecular mechanism remains largely unknown. Here, we found marked overexpression of FK506-binding protein 13 (FKBP13) in long-lived PCs from autoimmune mice and investigated its function using a plasmacytoma cell line secreting IgA. FKBP13 expression was induced largely in the lumen of ER in response to treatment with an ER stressor tunicamycin or overexpression of an adaptive unfolded protein response (UPR) protein X-box binding protein 1 (XBP1). Silencing of FKBP13 expression led to induction of molecules involved in the terminal UPR and ER stress-associated apoptosis. FKBP13 interacted with Ig, facilitated its ubiquitination, and lowered the extent of ER stress. FKBP13 overexpression caused a significant reduction in secreted IgA in plasmacytoma cells, and FKBP13 knockdown exerted an opposite effect. Rapamycin interfered with the interaction between FKBP13 and IgA and enhanced the amount of secreted IgA. Importantly, the level of FKBP13 was inversely correlated with the amount of secreted antibody in long-lived PCs from autoimmune mice. These results suggest that FKBP13 is a marker of long-lived PCs and a component of XBP1-dependent ER protein homeostasis. FKBP13 is likely to act as a molecular chaperone that delivers misfolded ER clients, including Ig, to ER-associated degradation, so reducing proteotoxic stress on the PC. Our data reveal a novel cytoprotective role for FKBP13 in long-lived PCs occurring at the expense of antibody production.
Collapse
Affiliation(s)
- Mini Jeong
- Laboratory of Autoimmunology, Department of Anatomy and Cell Biology, College of Medicine, Hanyang University , Seoul , South Korea
| | - Eunkyeong Jang
- Laboratory of Autoimmunology, Department of Anatomy and Cell Biology, College of Medicine, Hanyang University , Seoul , South Korea
| | - Suk San Choi
- Laboratory of Autoimmunology, Department of Anatomy and Cell Biology, College of Medicine, Hanyang University , Seoul , South Korea
| | - Changhoon Ji
- Protein Metabolism Medical Research Center, Department of Biomedical Sciences, College of Medicine, Seoul National University , Seoul , South Korea
| | - Kyungho Lee
- Department of Biological Sciences, Konkuk University , Seoul , South Korea
| | - Jeehee Youn
- Laboratory of Autoimmunology, Department of Anatomy and Cell Biology, College of Medicine, Hanyang University , Seoul , South Korea
| |
Collapse
|
|
39
|
Guthrie LN, Abiraman K, Plyler ES, Sprenkle NT, Gibson SA, McFarland BC, Rajbhandari R, Rowse AL, Benveniste EN, Meares GP. Attenuation of PKR-like ER Kinase (PERK) Signaling Selectively Controls Endoplasmic Reticulum Stress-induced Inflammation Without Compromising Immunological Responses. J Biol Chem 2016; 291:15830-40. [PMID: 27226638 DOI: 10.1074/jbc.m116.738021] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Indexed: 01/22/2023] Open
Abstract
Inflammation and endoplasmic reticulum (ER) stress are associated with many neurological diseases. ER stress is brought on by the accumulation of misfolded proteins in the ER, which leads to activation of the unfolded protein response (UPR), a conserved pathway that transmits signals to restore homeostasis or eliminate the irreparably damaged cell. We provide evidence that inhibition or genetic haploinsufficiency of protein kinase R-like endoplasmic reticulum kinase (PERK) can selectively control inflammation brought on by ER stress without impinging on UPR-dependent survival and adaptive responses or normal immune responses. Using astrocytes lacking one or both alleles of PERK or the PERK inhibitor GSK2606414, we demonstrate that PERK haploinsufficiency or partial inhibition led to reduced ER stress-induced inflammation (IL-6, CCL2, and CCL20 expression) without compromising prosurvival responses. In contrast, complete loss of PERK blocked canonical PERK-dependent UPR genes and promoted apoptosis. Reversal of eIF2α-mediated translational repression using ISRIB potently suppressed PERK-dependent inflammatory gene expression, indicating that the selective modulation of inflammatory gene expression by PERK inhibition may be linked to attenuation of eIF2α phosphorylation and reveals a previously unknown link between translational repression and transcription of inflammatory genes. Additionally, ER-stressed astrocytes can drive an inflammatory M1-like phenotype in microglia, and this can be attenuated with inhibition of PERK. Importantly, targeting PERK neither disrupted normal cytokine signaling in astrocytes or microglia nor impaired macrophage phagocytosis or T cell polarization. Collectively, this work suggests that targeting PERK may provide a means for selective immunoregulation in the context of ER stress without disrupting normal immune function.
Collapse
Affiliation(s)
- Lauren N Guthrie
- From the Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia 26505 and
| | - Kavitha Abiraman
- the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294
| | - Emily S Plyler
- From the Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia 26505 and
| | - Neil T Sprenkle
- From the Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia 26505 and
| | - Sara A Gibson
- the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294
| | - Braden C McFarland
- the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294
| | - Rajani Rajbhandari
- the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294
| | - Amber L Rowse
- the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294
| | - Etty N Benveniste
- the Department of Cell, Developmental, and Integrative Biology, University of Alabama, Birmingham, Alabama 35294
| | - Gordon P Meares
- From the Department of Microbiology, Immunology, and Cell Biology, West Virginia University, Morgantown, West Virginia 26505 and
| |
Collapse
|
|
40
|
Martins AS, Alves I, Helguero L, Domingues MR, Neves BM. The Unfolded Protein Response in Homeostasis and Modulation of Mammalian Immune Cells. Int Rev Immunol 2016; 35:457-476. [PMID: 27119724 DOI: 10.3109/08830185.2015.1110151] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The endoplasmic reticulum (ER) plays important roles in eukaryotic protein folding and lipid biosynthesis. Several exogenous and endogenous cellular sources of stress can perturb ER homeostasis leading to the accumulation of unfolded proteins in the lumen. Unfolded protein accumulation triggers a signal-transduction cascade known as the unfolded protein response (UPR), an adaptive mechanism which aims to protect cells from protein aggregates and to restore ER functions. Further to this protective mechanism, in immune cells, UPR molecular effectors have been shown to participate in a wide range of biological processes such as cell differentiation, survival and immunoglobulin and cytokine production. Recent findings also highlight the involvement of the UPR machinery in the maturational program and antigen presentation capacities of dendritic cells. UPR is therefore a key element in immune system homeostasis with direct implications on both adaptive and innate immune responses. The present review summarizes the knowledge on the emerging roles of UPR signaling cascades in mammalian immune cells as well as the consequences of their dysregulation in relation to the pathogenesis of several diseases.
Collapse
Affiliation(s)
- Ana Sofia Martins
- a Mass Spectrometry Centre, Department of Chemistry and QOPNA , University of Aveiro, Campus Universitário de Santiago , Aveiro , Portugal
| | - Inês Alves
- a Mass Spectrometry Centre, Department of Chemistry and QOPNA , University of Aveiro, Campus Universitário de Santiago , Aveiro , Portugal
| | - Luisa Helguero
- a Mass Spectrometry Centre, Department of Chemistry and QOPNA , University of Aveiro, Campus Universitário de Santiago , Aveiro , Portugal.,b Institute for Research in Biomedicine - iBiMED, Health Sciences Program, Universidade de Aveiro , Portugal
| | - Maria Rosário Domingues
- a Mass Spectrometry Centre, Department of Chemistry and QOPNA , University of Aveiro, Campus Universitário de Santiago , Aveiro , Portugal
| | - Bruno Miguel Neves
- a Mass Spectrometry Centre, Department of Chemistry and QOPNA , University of Aveiro, Campus Universitário de Santiago , Aveiro , Portugal.,c Faculty of Pharmacy and Centre for Neuroscience and Cell Biology, University of Coimbra , Coimbra , Portugal
| |
Collapse
|
|
41
|
Longo M, Spinelli R, D'Esposito V, Zatterale F, Fiory F, Nigro C, Raciti GA, Miele C, Formisano P, Beguinot F, Di Jeso B. Pathologic endoplasmic reticulum stress induced by glucotoxic insults inhibits adipocyte differentiation and induces an inflammatory phenotype. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2016; 1863:1146-56. [PMID: 26940722 DOI: 10.1016/j.bbamcr.2016.02.019] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Revised: 02/02/2016] [Accepted: 02/26/2016] [Indexed: 12/24/2022]
Abstract
Adipocyte differentiation is critical in obesity. By controlling new adipocyte recruitment, adipogenesis contrasts adipocyte hypertrophy and its adverse consequences, such as insulin resistance. Contrasting data are present in literature on the effect of endoplasmic reticulum (ER) stress and subsequent unfolded protein response (UPR) on adipocyte differentiation, being reported to be either necessary or inhibitory. In this study, we sought to clarify the effect of ER stress and UPR on adipocyte differentiation. We have used two different cell lines, the widely used pre-adipocyte 3T3-L1 cells and a murine multipotent mesenchymal cell line, W20-17 cells. A strong ER stress activator, thapsigargin, and a pathologically relevant inducer of ER stress, glucosamine (GlcN), induced ER stress and UPR above those occurring in the absence of perturbation and inhibited adipocyte differentiation. Very low concentrations of 4-phenyl butyric acid (PBA, a chemical chaperone) inhibited only the overactivation of ER stress and UPR elicited by GlcN, leaving unaltered the part physiologically activated during differentiation, and reversed the inhibitory effect of GlcN on differentiation. In addition, GlcN stimulated proinflammatory cytokine release and PBA prevented these effects. An inhibitor of NF-kB also reversed the effects of GlcN on cytokine release. These results indicate that while ER stress and UPR activation is "physiologically" activated during adipocyte differentiation, the "pathologic" part of ER stress activation, secondary to a glucotoxic insult, inhibits differentiation. In addition, such a metabolic insult, causes a shift of the preadipocyte/adipocyte population towards a proinflammatory phenotype.
Collapse
Affiliation(s)
- Michele Longo
- Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy
| | - Rosa Spinelli
- Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy
| | - Vittoria D'Esposito
- Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy
| | - Federica Zatterale
- Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy
| | - Francesca Fiory
- Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy
| | - Cecilia Nigro
- Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy
| | - Gregory A Raciti
- Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy
| | - Claudia Miele
- Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy
| | - Pietro Formisano
- Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy
| | - Francesco Beguinot
- Dipartimento di Scienze Mediche Traslazionali, Università "Federico II", °IEOS/CNR, via S. Pansini 5, 80131 Napoli, Italy
| | - Bruno Di Jeso
- Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, Università del Salento, Strada Monteroni, 73100 Lecce, Italy.
| |
Collapse
|
|
42
|
Fahl SP, Harris B, Coffey F, Wiest DL. Rpl22 Loss Impairs the Development of B Lymphocytes by Activating a p53-Dependent Checkpoint. THE JOURNAL OF IMMUNOLOGY 2016; 194:200-9. [PMID: 25416806 DOI: 10.4049/jimmunol.1402242] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Although ribosomal proteins facilitate the ribosome’s core function of translation, emerging evidence suggests that some ribosomal proteins are also capable of performing tissue-restricted functions either from within specialized ribosomes or from outside of the ribosome. In particular, we have previously demonstrated that germline ablation of the gene encoding ribosomal protein Rpl22 causes a selective and p53-dependent arrest of ab T cell progenitors at the b-selection checkpoint. We have now identified a crucial role for Rpl22 during early B cell development. Germline ablation of Rpl22 results in a reduction in the absolute number of B-lineage progenitors in the bone marrow beginning at the pro–B cell stage. Although Rpl22-deficient pro–B cells are hyporesponsive to IL-7, a key cytokine required for early B cell development, the arrest of B cell development does not result from disrupted IL-7 signaling. Instead, p53 induction appears to be responsible for the developmental defects, as Rpl22 deficiency causes increased expression of p53 and activation of downstream p53 target genes, and p53 deficiency rescues the defect in B cell development in Rpl22-deficient mice. Interestingly, the requirement for Rpl22 in the B cell lineage appears to be developmentally restricted, because Rpl22-deficient splenic B cells proliferate normally in response to Ag receptor and Toll receptor stimuli and undergo normal class-switch recombination. These results indicate that Rpl22 performs a critical, developmentally restricted role in supporting early B cell development by preventing p53 induction.
Collapse
Affiliation(s)
- Shawn P Fahl
- Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA 19111
| | - Bryan Harris
- Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA 19111
| | - Francis Coffey
- Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA 19111
| | - David L Wiest
- Immune Cell Development and Host Defense Program, Fox Chase Cancer Center, Philadelphia, PA 19111
| |
Collapse
|
|
43
|
Smith SM, Carew NT, Milcarek C. RNA polymerases in plasma cells trav-ELL2 the beat of a different drum. World J Immunol 2015; 5:99-112. [DOI: 10.5411/wji.v5.i3.99] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2015] [Revised: 08/19/2015] [Accepted: 11/17/2015] [Indexed: 02/05/2023] Open
Abstract
There is a major transformation in gene expression between mature B cells (including follicular, marginal zone, and germinal center cells) and antibody secreting cells (ASCs), i.e., ASCs, (including plasma blasts, splenic plasma cells, and long-lived bone marrow plasma cells). This significant change-over occurs to accommodate the massive amount of secretory-specific immunoglobulin that ASCs make and the export processes itself. It is well known that there is an up-regulation of a small number of ASC-specific transcription factors Prdm1 (B-lymphocyte-induced maturation protein 1), interferon regulatory factor 4, and Xbp1, and the reciprocal down-regulation of Pax5, Bcl6 and Bach2, which maintain the B cell program. Less well appreciated are the major alterations in transcription elongation and RNA processing occurring between B cells and ASCs. The three ELL family members ELL1, 2 and 3 have different protein sequences and potentially distinct cellular roles in transcription elongation. ELL1 is involved in DNA repair and small RNAs while ELL3 was previously described as either testis or stem-cell specific. After B cell stimulation to ASCs, ELL3 levels fall precipitously while ELL1 falls off slightly. ELL2 is induced at least 10-fold in ASCs relative to B cells. All of these changes cause the RNA Polymerase II in ASCs to acquire different properties, leading to differences in RNA processing and histone modifications.
Collapse
|
|
44
|
Induction of Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral Interleukin-6 by X-Box Binding Protein 1. J Virol 2015; 90:368-78. [PMID: 26491160 DOI: 10.1128/jvi.01192-15] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Accepted: 10/08/2015] [Indexed: 12/28/2022] Open
Abstract
UNLABELLED Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and a subset of multicentric Castleman disease (MCD). The KSHV life cycle has two principal gene repertoires, latent and lytic. KSHV viral interleukin-6 (vIL-6), an analog of human IL-6, is usually lytic; production of vIL-6 by involved plasmablasts is a central feature of KSHV-MCD. vIL-6 also plays a role in PEL and KS. We show that a number of plasmablasts from lymph nodes of patients with KSHV-MCD express vIL-6 but not ORF45, a KSHV lytic gene. We further show that vIL-6 is directly induced by the spliced (active) X-box binding protein-1 (XBP-1s), a transcription factor activated by endoplasmic reticulum (ER) stress and differentiation of B cells in lymph nodes. The promoter region of vIL-6 contains several potential XBP-response elements (XREs), and two of these elements in particular mediate the effect of XBP-1s. Mutation of these elements abrogates the response to XBP-1s but not to the KSHV replication and transcription activator (RTA). Also, XBP-1s binds to the vIL-6 promoter in the region of these XREs. Exposure of PEL cells to a chemical inducer of XBP-1s can induce vIL-6. Patient-derived PEL tumor cells that produce vIL-6 frequently coexpress XBP-1, and immunofluorescence staining of involved KSHV-MCD lymph nodes reveals that most plasmablasts expressing vIL-6 also coexpress XBP-1. These results provide evidence that XBP-1s is a direct activator of KSHV vIL-6 and that this is an important step in the pathogenesis of KSHV-MCD and PEL. IMPORTANCE Kaposi sarcoma herpesvirus (KSHV)-associated multicentric Castleman disease (KSHV-MCD) is characterized by severe inflammatory symptoms caused by an excess of cytokines, particularly KSHV-encoded viral interleukin-6 (vIL-6) produced by lymph node plasmablasts. vIL-6 is usually a lytic gene. We show that a number of KSHV-MCD lymph node plasmablasts express vIL-6 but do not have full lytic KSHV replication. Differentiating lymph node B cells express spliced (active) X-box binding protein-1 (XBP-1s). We show that XBP-1s binds to the promoter of vIL-6 and can directly induce production of vIL-6 through X-box protein response elements on the vIL-6 promoter region. We further show that chemical inducers of XBP-1s can upregulate production of vIL-6. Finally, we show that most vIL-6-producing plasmablasts from lymph nodes of KSHV-MCD patients coexpress XBP-1s. These results demonstrate that XBP-1s can directly induce vIL-6 and provide evidence that this is a key step in the pathogenesis of KSHV-MCD and other KSHV-induced diseases.
Collapse
|
|
45
|
Liu J, Zhou C, Tao X, Feng L, Wang X, Chen L, Li C, Huang D, Fang S, Shen Y. ER stress-inducible protein MANF selectively expresses in human spleen. Hum Immunol 2015; 76:823-30. [PMID: 26429332 DOI: 10.1016/j.humimm.2015.09.043] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2013] [Revised: 06/17/2015] [Accepted: 09/26/2015] [Indexed: 11/25/2022]
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF; also known as arginine-rich, mutated in early tumors; ARMET), is an ER stress-inducible protein, and widely expressed in mammalian tissues. In this study, we are interested in the profile of MANF expression in human splenocytes. Three patients with spleen trauma were enrolled in this study. Immunohistochemistry and immunofluorescence were used to detect MANF expression in the four types of cells, including T cells, B cells, plasma cells, and macrophages in spleens by using the specific antibodies of anti-CD3, anti-CD20, anti-CD138, and anti-CD68, respectively. We found that MANF-positive cells extensively distributed in the red pulp and marginal-zone of spleen, and MANF was almost localized in the cytoplasm of splenocytes. Double immunofluorescent staining results showed that MANF localized mainly in the plasma cells and macrophages, but not in T and B cells. Meanwhile, we found that some MANF-positive cells expressed ER stress-related proteins, including ATF6, XBP1s, BiP, and CHOP. These results suggest that the selective expression of MANF in splenocytes may be involved in plasma cell differentiation and immune regulation.
Collapse
Affiliation(s)
- Jun Liu
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China; School of Pharmacy, Anhui Medical University, Hefei 230032, China; Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Chengyue Zhou
- The 4th Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Xiaofang Tao
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China; Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Lijie Feng
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China; Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Xia Wang
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China; Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Lijian Chen
- The First Affiliated Hospital of Anhui Medical University, Hefei 230032, China
| | - Chengjin Li
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China; Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Dake Huang
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China
| | - Shengyun Fang
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China; Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China
| | - Yuxian Shen
- School of Basic Medical Sciences, Anhui Medical University, Hefei 230032, China; Biopharmaceutical Research Institute, Anhui Medical University, Hefei 230032, China.
| |
Collapse
|
|
46
|
Stone S, Lin W. The unfolded protein response in multiple sclerosis. Front Neurosci 2015; 9:264. [PMID: 26283904 PMCID: PMC4518158 DOI: 10.3389/fnins.2015.00264] [Citation(s) in RCA: 72] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 07/14/2015] [Indexed: 01/08/2023] Open
Abstract
The unfolded protein response (UPR) occurs in response to endoplasmic reticulum (ER) stress caused by the accumulation of unfolded or misfolded proteins in the ER. The UPR is comprised of three signaling pathways that promote cytoprotective functions to correct ER stress; however, if ER stress cannot be resolved the UPR results in apoptosis of affected cells. The UPR is an important feature of various human diseases, including multiple sclerosis (MS). Recent studies have shown several components of the UPR are upregulated in the multiple cell types in MS lesions, including oligodendrocytes, T cells, microglia/macrophages, and astrocytes. Data from animal model studies, particularly studies of experimental autoimmune encephalomyelitis (EAE) and the cuprizone model, imply an important role of the UPR activation in oligodendrocytes in the development of MS. In this review we will cover current literature on the UPR and the evidence for its role in the development of MS.
Collapse
Affiliation(s)
- Sarrabeth Stone
- Department of Neuroscience, University of Minnesota Minneapolis, MN, USA ; Institute for Translational Neuroscience, University of Minnesota Minneapolis, MN, USA
| | - Wensheng Lin
- Department of Neuroscience, University of Minnesota Minneapolis, MN, USA ; Institute for Translational Neuroscience, University of Minnesota Minneapolis, MN, USA
| |
Collapse
|
|
47
|
Zuo T, Cao L, Sun X, Li X, Wu J, Lu S, Xue C, Tang Q. Dietary squid ink polysaccharide could enhance SIgA secretion in chemotherapeutic mice. Food Funct 2015; 5:3189-96. [PMID: 25308407 DOI: 10.1039/c4fo00569d] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Secretory immunoglobulin A (SIgA) is a non-inflammatory antibody that shields internal body surfaces, such as in the intestine to neutralize pathogens in the lumen of the intestine. As chemotherapy seriously damages the mucosal immune system, we herein demonstrated that polysaccharide from the squid ink of Ommastrephes bartrami (OBP) activated intestinal SIgA secretion to prevent chemotherapeutic injury. Using a mouse model of chemotherapy induced intestinal injury by intraperitoneal injection of 50 mg kg(-1) cyclophosphamide, our results showed an enhanced SIgA concentration in intestinal mucosa by OBP administration and the higher production of SIgA relied on the greater expression of IgA, J chain and pIgR. Furthermore, the higher expressions of IL-6, IL-10 and TNF-α increased by OBP treatment contributed to enhanced IgA and J chain synthesis in IgA(+) plasma cells, and pIgR expression in epithelial cells. It also triggered a prompt immunoglobulin secretory pathway confirmed by enhanced UPR (unfolded protein response) effectors XBP-1s and Bip expression. Our results have important implications for the mucosal immunity enhancement effects of OBP as a functional food component for chemotherapeutic patients.
Collapse
Affiliation(s)
- Tao Zuo
- College of Food Science and Engineering, Ocean University of China, Yushan Road 5th, Qingdao, Shandong Province, P.R. China266003
| | | | | | | | | | | | | | | |
Collapse
|
|
48
|
Sanderson TH, Gallaway M, Kumar R. Unfolding the unfolded protein response: unique insights into brain ischemia. Int J Mol Sci 2015; 16:7133-42. [PMID: 25830481 PMCID: PMC4425008 DOI: 10.3390/ijms16047133] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Revised: 03/19/2015] [Accepted: 03/27/2015] [Indexed: 01/07/2023] Open
Abstract
The endoplasmic reticulum (ER) is responsible for processing of proteins that are destined to be secreted, enclosed in a vesicle, or incorporated in the plasma membrane. Nascent peptides that enter the ER undergo a series of highly regulated processing steps to reach maturation as they transit the ER. Alterations in the intracellular environment that induce ER stress are thought to interrupt these processing steps, and result in unfolding of proteins in the ER. Accumulation of unfolded proteins concurrently activates three transmembrane stress sensors, IRE1, ATF6 and PERK, and is referred to as the Unfolded Protein Response (UPR). Our understanding of the mechanisms of UPR induction has been assembled primarily from experiments inducing ER stress with chemical and genetic manipulations. However, physiological stress often induces activation of ER stress sensors in a distinct manner from the canonical UPR. The unique activation profiles in vivo have prompted us to examine the mechanism of UPR activation in neurons following cerebral ischemia.
Collapse
Affiliation(s)
- Thomas H Sanderson
- Cardiovascular Research Institute and Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48201, USA.
| | - Molly Gallaway
- Department of Emergency Medicine, Wayne State University School of Medicine, Detroit, MI 48201, USA.
| | - Rita Kumar
- Cardiovascular Research Institute and Departments of Emergency Medicine and Physiology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
| |
Collapse
|
|
49
|
p58IPK is an inhibitor of the eIF2α kinase GCN2 and its localization and expression underpin protein synthesis and ER processing capacity. Biochem J 2015; 465:213-25. [PMID: 25329545 DOI: 10.1042/bj20140852] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
One of the key cellular responses to stress is the attenuation of mRNA translation and protein synthesis via the phosphorylation of eIF2α (eukaryotic translation initiation factor 2α). This is mediated by four eIF2α kinases and it has been suggested that each kinase is specific to the cellular stress imposed. In the present study, we show that both PERK (PKR-like endoplasmic reticulum kinase/eIF2α kinase 3) and GCN2 (general control non-derepressible 2/eIF2α kinase 4) are required for the stress responses associated with conditions encountered by cells overexpressing secreted recombinant protein. Importantly, whereas GCN2 is the kinase that is activated following cold-shock/hypothermic culturing of mammalian cells, PERK and GCN2 have overlapping functions since knockdown of one of these at the mRNA level is compensated for by the cell by up-regulating levels of the other. The protein p58IPK {also known as DnaJ3C [DnaJ heat-shock protein (hsp) 40 homologue, subfamily C, member 3]} is known to inhibit the eIF2α kinases PKR (dsRNA-dependent protein kinase/eIF2α kinase 2) and PERK and hence prevent or delay eIF2α phosphorylation and consequent inhibition of translation. However, we show that p58IPK is a general inhibitor of the eIF2α kinases in that it also interacts with GCN2. Thus forced overexpression of cytoplasmic p58 delays eIF2α phosphorylation, suppresses GCN2 phosphorylation and prolongs protein synthesis under endoplasmic reticulum (ER), hypothermic and prolonged culture stress conditions. Taken together, our data suggest that there is considerable cross talk between the eIF2α kinases to ensure that protein synthesis is tightly regulated. Their activation is controlled by p58 and the expression levels and localization of this protein are crucial in the capacity the cells to respond to cellular stress via control of protein synthesis rates and subsequent folding in the ER.
Collapse
|
|
50
|
Schinzel R, Dillin A. Endocrine aspects of organelle stress—cell non-autonomous signaling of mitochondria and the ER. Curr Opin Cell Biol 2015; 33:102-10. [PMID: 25677685 DOI: 10.1016/j.ceb.2015.01.006] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Accepted: 01/23/2015] [Indexed: 12/12/2022]
Abstract
Organisms have to cope with an unpredictable and dynamic environment. It is crucial for any living being to respond to these changes by buffering the effects on cellular homeostasis. Failure to appropriately respond to stress can have severe consequences for health and survival. Eukaryotic cells possess several organelle-specific stress responses to cope with this challenge. Besides their central role in stress resistance, these pathways have also been shown to be important in the regulation of proteome maintenance, development and longevity. Intriguingly, many of these effects seem to be controlled by only a subset of cells implying a systemic regulation in a cell non-autonomous manner. The understanding of the nature of this stress communication across tissues, its mechanisms and impact, will be paramount in understanding disease etiology and the development of therapeutic strategies.
Collapse
Affiliation(s)
- Robert Schinzel
- Department of Molecular and Cell Biology, The University of California, Berkeley, Li Ka Shing Center for Biomedical and Health Sciences, USA
| | - Andrew Dillin
- Department of Molecular and Cell Biology, The University of California, Berkeley, Li Ka Shing Center for Biomedical and Health Sciences, USA; Howard Hughes Medical Institute, The University of California, Berkeley, USA.
| |
Collapse
|