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.
authors: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors: Sinyi
authors: S
authors: Kong
authors: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province, 215123, China;
authors: Yi
authors: Y
authors: Yang
authors: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors: Yuanming
authors: Y
authors: Xu
authors: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; Department of Pediatrics, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China;
authors: Yajun
authors: Y
authors: Wang
authors: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors: Yusi
authors: Y
authors: Zhang
authors: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors: Johanna
authors: J
authors: Melo-Cardenas
authors: Department of Pediatrics, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, China;
authors: Xiangping
authors: X
authors: Xu
authors: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors: Beixue
authors: B
authors: Gao
authors: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors: Edward B
authors: EB
authors: Thorp
authors: Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ 85721;
authors: Donna D
authors: DD
authors: Zhang
authors: Robert H. Lurie Comprehensive Cancer Center, Department of Medicine-Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611;
authors: Bin
authors: B
authors: Zhang
authors: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, PA;
authors: Jianxun
authors: J
authors: Song
authors: Center for Molecular Medicine and Genetics, Department of Immunology and Microbiology, Wayne State University School of Medicine, Detroit, MI 48201;
authors: Kezhong
authors: K
authors: Zhang
authors: School of Life Science and Medicine, Dalian University of Technology, Dalian, 116024, China;
authors: Jianning
authors: J
authors: Zhang
authors: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province, 215123, China; fangD@northwestern.edu j_pzhang@suda.edu.cn allergyli@163.com.
authors: Jinping
authors: J
authors: Zhang
authors: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province, 215123, China; Shanghai Key Laboratory of Translational Medicine on Ear and Nose Diseases, Department of Otolaryngology, Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200092, China fangD@northwestern.edu j_pzhang@suda.edu.cn allergyli@163.com.
authors: Huabin
authors: H
authors: Li
authors: Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611; fangD@northwestern.edu j_pzhang@suda.edu.cn allergyli@163.com.
authors: Deyu
authors: D
authors: Fang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000201:enzymology; D053222:Fas Ligand Protein / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D059748:Proteolysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics* / Q000378:metabolism
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D019014:fas Receptor; C498235:Syvn1 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: B cells; Fas; Hrd1; ubiquitination