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

doi:10.1073/pnas.1606742113

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 journal › Article › peer-review

31 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 language	English (US)
Pages (from-to)	10394-10399
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	113
Issue number	37
DOIs	https://doi.org/10.1073/pnas.1606742113
State	Published - Sep 13 2016

Keywords

B cells
Fas
Hrd1
Ubiquitination

ASJC Scopus subject areas

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10.1073/pnas.1606742113

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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

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 et al.
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 journal › Article › peer-review

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

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title = "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.",

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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",

note = "Funding Information: 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.).",

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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

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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

N1 - Funding Information: 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.).

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

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