Regnase-1 is an emerging regulator of immune responses with essential roles in the posttranscriptional control of immune cell activation. Regnase-1 is expressed in B cells; however, its B cell–specific functions remain unknown. Here, we demonstrate that Regnase-1 prevents severe autoimmune pathology and show its essential role in maintaining B cell homeostasis. Using Cre driver mice for ablation of Regnase-1 at various stages of B cell development, we demonstrate that loss of Regnase-1 leads to aberrant B cell activation and differentiation, resulting in systemic autoimmunity and early morbidity. The basis of these findings was informed by gene expression data revealing a regulatory role for Regnase-1 in the suppression of a transcriptional program that promotes B cell activation, survival, and differentiation. Overall, our study shows that Regnase-1 exerts critical control of B cell activation, which is required for prevention of immunopathology.
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April 02 2021
Regnase-1 is essential for B cell homeostasis to prevent immunopathology
Numana Bhat
,
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
Correspondence to Numana Bhat: numana.bhat@gmail.com
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Richard Virgen-Slane
,
Richard Virgen-Slane
Formal analysis, Software, Visualization, Writing - review & editing
3
Laboratory of Molecular Immunology, Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
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Parham Ramezani-Rad
,
Parham Ramezani-Rad
Conceptualization, Investigation, Resources, Validation, Visualization, Writing - review & editing
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
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Charlotte R. Leung
,
Charlotte R. Leung
Investigation
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
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Cindi Chen
,
Cindi Chen
Investigation
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
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Daniel Balsells
,
Daniel Balsells
Investigation
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
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Ashima Shukla
,
Ashima Shukla
Investigation
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
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Elaine Kao
,
Elaine Kao
Investigation
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
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John R. Apgar
,
John R. Apgar
Conceptualization, Project administration, Resources, Supervision
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
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Mingui Fu
,
Mingui Fu
Resources
2
Department of Biomedical Science and Shock/Trauma Research Center, School of Medicine, University of Missouri–Kansas City, Kansas City, MO
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Carl F. Ware
,
Carl F. Ware
Conceptualization, Funding acquisition, Project administration, Supervision, Writing - review & editing
3
Laboratory of Molecular Immunology, Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
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Robert C. Rickert
Robert C. Rickert
Conceptualization, Funding acquisition, Project administration, Supervision, Writing - review & editing
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
Search for other works by this author on:
Numana Bhat
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Visualization, Writing - original draft, Writing - review & editing
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
Richard Virgen-Slane
Formal analysis, Software, Visualization, Writing - review & editing
3
Laboratory of Molecular Immunology, Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
Parham Ramezani-Rad
Conceptualization, Investigation, Resources, Validation, Visualization, Writing - review & editing
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
Charlotte R. Leung
Investigation
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
Cindi Chen
Investigation
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
Daniel Balsells
Investigation
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
Ashima Shukla
Investigation
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
Elaine Kao
Investigation
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
John R. Apgar
Conceptualization, Project administration, Resources, Supervision
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
Mingui Fu
Resources
2
Department of Biomedical Science and Shock/Trauma Research Center, School of Medicine, University of Missouri–Kansas City, Kansas City, MO
Carl F. Ware
Conceptualization, Funding acquisition, Project administration, Supervision, Writing - review & editing
3
Laboratory of Molecular Immunology, Infectious and Inflammatory Diseases Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
Robert C. Rickert
Conceptualization, Funding acquisition, Project administration, Supervision, Writing - review & editing
1
Tumor Microenvironment and Cancer Immunology Program, National Cancer Institute designated Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA
Correspondence to Numana Bhat: numana.bhat@gmail.com
Disclosures: C.F. Ware reported grants from NIH and grants from Perkins Foundation during the conduct of the study; and grants from E. Lilly Co., grants from Boehringer Ingelheim Co., personal fees from Coherus Inc, grants from Capella Biosciences, and personal fees from Capella Biosciences outside the submitted work. No other disclosures were reported.
Received:
May 12 2020
Revision Received:
January 06 2021
Accepted:
February 22 2021
Online Issn: 1540-9538
Print Issn: 0022-1007
Funding:
National Institutes of Health
(AI122344)
© 2021 Bhat et al.
2021
This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).
J Exp Med (2021) 218 (5): e20200971.
Article history
Received:
May 12 2020
Revision Received:
January 06 2021
Accepted:
February 22 2021
Citation
Numana Bhat, Richard Virgen-Slane, Parham Ramezani-Rad, Charlotte R. Leung, Cindi Chen, Daniel Balsells, Ashima Shukla, Elaine Kao, John R. Apgar, Mingui Fu, Carl F. Ware, Robert C. Rickert; Regnase-1 is essential for B cell homeostasis to prevent immunopathology. J Exp Med 3 May 2021; 218 (5): e20200971. doi: https://doi.org/10.1084/jem.20200971
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