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Gammaherpesvirus-mediated repression reveals EWSR1 to be a negative regulator of B cell responses

The germinal center (GC) plays a central role in the generation of antigen-specific B cells and antibodies. Tight regulation of the GC is essential due to the inherent risks of tumorigenesis and autoimmunity posed by inappropriate GC B cell processes. Gammaherpesviruses such as Epstein–Barr virus (E...

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Autores principales: Wang, Yiping, Feswick, April, Apostolou, Vasiliki, Petkov, Petko M., Moser, Emily K., Tibbetts, Scott A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9371696/
https://www.ncbi.nlm.nih.gov/pubmed/35921433
http://dx.doi.org/10.1073/pnas.2123362119
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author Wang, Yiping
Feswick, April
Apostolou, Vasiliki
Petkov, Petko M.
Moser, Emily K.
Tibbetts, Scott A.
author_facet Wang, Yiping
Feswick, April
Apostolou, Vasiliki
Petkov, Petko M.
Moser, Emily K.
Tibbetts, Scott A.
author_sort Wang, Yiping
collection PubMed
description The germinal center (GC) plays a central role in the generation of antigen-specific B cells and antibodies. Tight regulation of the GC is essential due to the inherent risks of tumorigenesis and autoimmunity posed by inappropriate GC B cell processes. Gammaherpesviruses such as Epstein–Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68) utilize numerous armaments to drive infected naïve B cells, independent of antigen, through GC reactions to expand the latently infected B cell population and establish a stable latency reservoir. We previously demonstrated that the MHV68 microRNA (miRNA) mghv-miR-M1-7-5p represses host EWSR1 (Ewing sarcoma breakpoint region 1) to promote B cell infection. EWSR1 is a transcription and splicing regulator that is recognized for its involvement as a fusion protein in Ewing sarcoma. A function for EWSR1 in B cell responses has not been previously reported. Here, we demonstrate that 1) B cell–specific deletion of EWSR1 had no effect on generation of mature B cell subsets or basal immunoglobulin levels in naïve mice, 2) repression or ablation of EWSR1 in B cells promoted expansion of MHV68 latently infected GC B cells, and 3) B cell–specific deletion of EWSR1 during a normal immune response to nonviral antigen resulted in significantly elevated numbers of antigen-specific GC B cells, plasma cells, and circulating antibodies. Notably, EWSR1 deficiency did not affect the proliferation or survival of GC B cells but instead resulted in the generation of increased numbers of precursor GC B cells. Cumulatively, these findings demonstrate that EWSR1 is a negative regulator of B cell responses.
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spelling pubmed-93716962023-02-03 Gammaherpesvirus-mediated repression reveals EWSR1 to be a negative regulator of B cell responses Wang, Yiping Feswick, April Apostolou, Vasiliki Petkov, Petko M. Moser, Emily K. Tibbetts, Scott A. Proc Natl Acad Sci U S A Biological Sciences The germinal center (GC) plays a central role in the generation of antigen-specific B cells and antibodies. Tight regulation of the GC is essential due to the inherent risks of tumorigenesis and autoimmunity posed by inappropriate GC B cell processes. Gammaherpesviruses such as Epstein–Barr virus (EBV) and murine gammaherpesvirus 68 (MHV68) utilize numerous armaments to drive infected naïve B cells, independent of antigen, through GC reactions to expand the latently infected B cell population and establish a stable latency reservoir. We previously demonstrated that the MHV68 microRNA (miRNA) mghv-miR-M1-7-5p represses host EWSR1 (Ewing sarcoma breakpoint region 1) to promote B cell infection. EWSR1 is a transcription and splicing regulator that is recognized for its involvement as a fusion protein in Ewing sarcoma. A function for EWSR1 in B cell responses has not been previously reported. Here, we demonstrate that 1) B cell–specific deletion of EWSR1 had no effect on generation of mature B cell subsets or basal immunoglobulin levels in naïve mice, 2) repression or ablation of EWSR1 in B cells promoted expansion of MHV68 latently infected GC B cells, and 3) B cell–specific deletion of EWSR1 during a normal immune response to nonviral antigen resulted in significantly elevated numbers of antigen-specific GC B cells, plasma cells, and circulating antibodies. Notably, EWSR1 deficiency did not affect the proliferation or survival of GC B cells but instead resulted in the generation of increased numbers of precursor GC B cells. Cumulatively, these findings demonstrate that EWSR1 is a negative regulator of B cell responses. National Academy of Sciences 2022-08-03 2022-08-09 /pmc/articles/PMC9371696/ /pubmed/35921433 http://dx.doi.org/10.1073/pnas.2123362119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Wang, Yiping
Feswick, April
Apostolou, Vasiliki
Petkov, Petko M.
Moser, Emily K.
Tibbetts, Scott A.
Gammaherpesvirus-mediated repression reveals EWSR1 to be a negative regulator of B cell responses
title Gammaherpesvirus-mediated repression reveals EWSR1 to be a negative regulator of B cell responses
title_full Gammaherpesvirus-mediated repression reveals EWSR1 to be a negative regulator of B cell responses
title_fullStr Gammaherpesvirus-mediated repression reveals EWSR1 to be a negative regulator of B cell responses
title_full_unstemmed Gammaherpesvirus-mediated repression reveals EWSR1 to be a negative regulator of B cell responses
title_short Gammaherpesvirus-mediated repression reveals EWSR1 to be a negative regulator of B cell responses
title_sort gammaherpesvirus-mediated repression reveals ewsr1 to be a negative regulator of b cell responses
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9371696/
https://www.ncbi.nlm.nih.gov/pubmed/35921433
http://dx.doi.org/10.1073/pnas.2123362119
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