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Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas.


ABSTRACT: Humoral immunity involves multiple checkpoints during B-cell development, maturation, and activation. The cell death receptor CD95/Fas-mediated apoptosis plays a critical role in eliminating the unwanted activation of B cells by self-reactive antigens and in maintaining B-cell homeostasis through activation-induced B-cell death (AICD). The molecular mechanisms controlling AICD remain largely undefined. Herein, we show that the E3 ubiquitin ligase Hrd1 protected B cells from activation-induced cell death by degrading the death receptor Fas. Hrd1-null B cells exhibited high Fas expression during activation and rapidly underwent Fas-mediated apoptosis, which could be largely inhibited by FasL neutralization. Fas mutation in Hrd1 KO mice abrogated the increase in B-cell AICD. We identified Hrd1 as the first E3 ubiquitin ligase of the death receptor Fas and Hrd1-mediated Fas destruction as a molecular mechanism in regulating B-cell immunity.

SUBMITTER: Kong S 

PROVIDER: S-EPMC5027446 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas.

Kong Sinyi S   Yang Yi Y   Xu Yuanming Y   Wang Yajun Y   Zhang Yusi Y   Melo-Cardenas Johanna J   Xu Xiangping X   Gao Beixue B   Thorp Edward B EB   Zhang Donna D DD   Zhang Bin B   Song Jianxun J   Zhang Kezhong K   Zhang Jianning J   Zhang Jinping J   Li Huabin H   Fang Deyu D  

Proceedings of the National Academy of Sciences of the United States of America 20160829 37


Humoral immunity involves multiple checkpoints during B-cell development, maturation, and activation. The cell death receptor CD95/Fas-mediated apoptosis plays a critical role in eliminating the unwanted activation of B cells by self-reactive antigens and in maintaining B-cell homeostasis through activation-induced B-cell death (AICD). The molecular mechanisms controlling AICD remain largely undefined. Herein, we show that the E3 ubiquitin ligase Hrd1 protected B cells from activation-induced ce  ...[more]

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