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*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 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

Funding

We thank Dr. Ira Tabas (Richard J. Stock Professor and Vice-Chairman of Research, Department of Medicine, Columbia University) for the CHOP-floxed mice. We thank members of the D.F. Laboratory for critical reading of the manuscript and constructive suggestions during our research. This work was supported by NIH R01 Grants AI079056, AI108634 and AR006634 (to D.F.).

Keywords

  • B cells
  • Fas
  • Hrd1
  • Ubiquitination

ASJC Scopus subject areas

  • General

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