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

Authors: Kong, Sinyi; Yang, Yi; Xu, Yuanming; Wang, Yajun; Zhang, Yusi; Melo-Cardenas, Johanna; Xu, Xiangping; Gao, Beixue; Thorp, Edward B; Zhang, Donna D; Zhang, Bin; Song, Jianxun; Zhang, Kezhong; Zhang, Jianning; Zhang, Jinping; Li, Huabin; Fang, Deyu

Published In Proc Natl Acad Sci U S A, (2016 09 13)

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.

PubMed ID: 27573825 Exiting the NIEHS site

MeSH Terms: Animals; Apoptosis/genetics; Apoptosis/immunology; B-Lymphocytes/immunology; Endoplasmic Reticulum/enzymology; Fas Ligand Protein/genetics*; Lymphocyte Activation/genetics*; Lymphocyte Activation/immunology; Mice; Mice, Knockout; Proteolysis; Ubiquitin-Protein Ligases/genetics*; Ubiquitin-Protein Ligases/immunology; Ubiquitin-Protein Ligases/metabolism; fas Receptor/genetics*; fas Receptor/metabolism

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