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

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

Research output: Contribution to journalArticle

16 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)10394-10399
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number37
DOIs
StatePublished - Sep 13 2016

Keywords

  • B cells
  • Fas
  • Hrd1
  • Ubiquitination

ASJC Scopus subject areas

  • General

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    Kong, S., Yang, Y., Xu, Y., Wang, Y., Zhang, Y., Melo-Cardenas, J., Xu, X., Gao, B., Thorp, E. B., Zhang, D. D., Zhang, B., Song, J., Zhang, K., Zhang, J., Zhang, J., Li, H., & Fang, D. (2016). Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas. Proceedings of the National Academy of Sciences of the United States of America, 113(37), 10394-10399. https://doi.org/10.1073/pnas.1606742113