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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...

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Autores principales: Davidzohn, Natalia, Biram, Adi, Stoler-Barak, Liat, Grenov, Amalie, Dassa, Bareket, Shulman, Ziv
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Rockefeller University Press 2019
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.
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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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