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Syk degradation restrains plasma cell formation and promotes zonal transitions in germinal centers
Germinal centers (GCs) are sites at which B cells proliferate and mutate their antibody-encoding genes in the dark zone (DZ), followed by affinity-based selection in the light zone (LZ). B cell antigen receptor (BCR) signals induce Syk activation followed by rapid phosphatase-mediated desensitizatio...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062533/ https://www.ncbi.nlm.nih.gov/pubmed/31873727 http://dx.doi.org/10.1084/jem.20191043 |
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author | Davidzohn, Natalia Biram, Adi Stoler-Barak, Liat Grenov, Amalie Dassa, Bareket Shulman, Ziv |
author_facet | Davidzohn, Natalia Biram, Adi Stoler-Barak, Liat Grenov, Amalie Dassa, Bareket Shulman, Ziv |
author_sort | Davidzohn, Natalia |
collection | PubMed |
description | Germinal centers (GCs) are sites at which B cells proliferate and mutate their antibody-encoding genes in the dark zone (DZ), followed by affinity-based selection in the light zone (LZ). B cell antigen receptor (BCR) signals induce Syk activation followed by rapid phosphatase-mediated desensitization; however, how degradation events regulate BCR functions in GCs is unclear. Here, we found that Syk degradation restrains plasma cell (PC) formation in GCs and promotes B cell LZ to DZ transition. Using a mouse model defective in Cbl-mediated Syk degradation, we demonstrate that this machinery attenuates BCR signaling intensity by mitigating the Kras/Erk and PI3K/Foxo1 pathways, and restricting the expression of PC transcription factors in GC B cells. Inhibition of Syk degradation perturbed gene expression, specifically in the LZ, and enhanced the generation of PCs without affecting B cell proliferation. These findings reveal how long-lasting attenuation of signal transduction by degradation events regulates cell fate within specialized microanatomical sites. |
format | Online Article Text |
id | pubmed-7062533 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-70625332020-09-02 Syk degradation restrains plasma cell formation and promotes zonal transitions in germinal centers Davidzohn, Natalia Biram, Adi Stoler-Barak, Liat Grenov, Amalie Dassa, Bareket Shulman, Ziv J Exp Med Research Articles Germinal centers (GCs) are sites at which B cells proliferate and mutate their antibody-encoding genes in the dark zone (DZ), followed by affinity-based selection in the light zone (LZ). B cell antigen receptor (BCR) signals induce Syk activation followed by rapid phosphatase-mediated desensitization; however, how degradation events regulate BCR functions in GCs is unclear. Here, we found that Syk degradation restrains plasma cell (PC) formation in GCs and promotes B cell LZ to DZ transition. Using a mouse model defective in Cbl-mediated Syk degradation, we demonstrate that this machinery attenuates BCR signaling intensity by mitigating the Kras/Erk and PI3K/Foxo1 pathways, and restricting the expression of PC transcription factors in GC B cells. Inhibition of Syk degradation perturbed gene expression, specifically in the LZ, and enhanced the generation of PCs without affecting B cell proliferation. These findings reveal how long-lasting attenuation of signal transduction by degradation events regulates cell fate within specialized microanatomical sites. Rockefeller University Press 2019-12-24 /pmc/articles/PMC7062533/ /pubmed/31873727 http://dx.doi.org/10.1084/jem.20191043 Text en © 2019 Davidzohn et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/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/). |
spellingShingle | Research Articles Davidzohn, Natalia Biram, Adi Stoler-Barak, Liat Grenov, Amalie Dassa, Bareket Shulman, Ziv Syk degradation restrains plasma cell formation and promotes zonal transitions in germinal centers |
title | Syk degradation restrains plasma cell formation and promotes zonal transitions in germinal centers |
title_full | Syk degradation restrains plasma cell formation and promotes zonal transitions in germinal centers |
title_fullStr | Syk degradation restrains plasma cell formation and promotes zonal transitions in germinal centers |
title_full_unstemmed | Syk degradation restrains plasma cell formation and promotes zonal transitions in germinal centers |
title_short | Syk degradation restrains plasma cell formation and promotes zonal transitions in germinal centers |
title_sort | syk degradation restrains plasma cell formation and promotes zonal transitions in germinal centers |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062533/ https://www.ncbi.nlm.nih.gov/pubmed/31873727 http://dx.doi.org/10.1084/jem.20191043 |
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