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

11 Citations (Scopus)

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

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Death Domain Receptors
Ubiquitin-Protein Ligases
Endoplasmic Reticulum
Immunity
B-Lymphocytes
Cell Death
Apoptosis
Null Lymphocytes
Autoantigens
Humoral Immunity
Homeostasis

All Science Journal Classification (ASJC) codes

  • General

Cite this

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. / Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas. In: Proceedings of the National Academy of Sciences of the United States of America. 2016 ; Vol. 113, No. 37. pp. 10394-10399.
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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.",
author = "Sinyi Kong and Yi Yang and Yuanming Xu and Yajun Wang and Yusi Zhang and Johanna Melo-Cardenas and Xiangping Xu and Beixue Gao and Thorp, {Edward B.} and Zhang, {Donna D.} and Bin Zhang and Jianxun Song and Kezhong Zhang and Jianning Zhang and Jinping Zhang and Huabin Li and Deyu Fang",
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Kong, S, Yang, Y, Xu, Y, Wang, Y, Zhang, Y, Melo-Cardenas, J, Xu, X, Gao, B, Thorp, EB, Zhang, DD, 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, vol. 113, no. 37, pp. 10394-10399. https://doi.org/10.1073/pnas.1606742113

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

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 113, No. 37, 13.09.2016, p. 10394-10399.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Endoplasmic reticulum-resident E3 ubiquitin ligase Hrd1 controls B-cell immunity through degradation of the death receptor CD95/Fas

AU - Kong, Sinyi

AU - Yang, Yi

AU - Xu, Yuanming

AU - Wang, Yajun

AU - Zhang, Yusi

AU - Melo-Cardenas, Johanna

AU - Xu, Xiangping

AU - Gao, Beixue

AU - Thorp, Edward B.

AU - Zhang, Donna D.

AU - Zhang, Bin

AU - Song, Jianxun

AU - Zhang, Kezhong

AU - Zhang, Jianning

AU - Zhang, Jinping

AU - Li, Huabin

AU - Fang, Deyu

PY - 2016/9/13

Y1 - 2016/9/13

N2 - 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.

AB - 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.

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