title: The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity.
abstract: Identification of positive regulators of T-cell immunity induced during autoimmune diseases is critical for developing novel therapies. The endoplasmic reticulum resident ubiquitin ligase Hrd1 has recently emerged as a critical regulator of dendritic cell antigen presentation, but its role in T-cell immunity is unknown. Here we show that genetic deletion of Hrd1 in mice inhibits T-cell proliferation, production of IL-2, and differentiation of Th1 and Th17 cells, and consequently protects mice from experimental autoimmune encephalomyelitis. Hrd1 facilitates T-cell proliferation by the destruction of cyclin-dependent kinase inhibitor p27(kip1), and deletion of p27(kip1) in Hrd1-null T-cells rescues proliferative capacity but not the production of cytokines, including IL-2, IFN-γ and IL-17. T-cell expression of Hrd1 is higher in patients with multiple sclerosis than in healthy individuals, and knockdown of Hrd1 in human CD4(+) T cells inhibits activation and differentiation to Th1 and Th17 cells. Our study identifies Hrd1 as a previously unappreciated positive regulator of T cells and implies that Hrd1 is a potential therapeutic target for autoimmune diseases.
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Chicago, Illinois 60611, USA.
authors.forename: Yuanming
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Chicago, Illinois 60611, USA.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhao
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Chicago, Illinois 60611, USA.|Allergy Center, Department of Otolaryngology-Head and Neck Surgery, Affiliated Eye and ENT Hospital, Fudan University, Shanghai 200031, China.
authors.forename: Quan
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: Allergy Center, Department of Otolaryngology-Head and Neck Surgery, Affiliated Eye and ENT Hospital, Fudan University, Shanghai 200031, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Chicago, Illinois 60611, USA.
authors.forename: Juncheng
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Chicago, Illinois 60611, USA.
authors.forename: Qingfei
authors.initials: Q
authors.lastname: Kong
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Chicago, Illinois 60611, USA.
authors.forename: Beixue
authors.initials: B
authors.lastname: Gao
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Chicago, Illinois 60611, USA.
authors.forename: Johanna
authors.initials: J
authors.lastname: Melo-Cardenas
authors.affiliation: Robert H. Lurie Comprehensive Cancer Center, Department of Medicine-Division of Hematology/Oncology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province 215123, China.
authors.forename: Jinping
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Microbiology and Immunology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
authors.forename: Jianxun
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizon 85721, USA.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry, School of Life Science and Medicine, Dalian University of Technology, 2 Linggong Road, Dalian 116024, China.
authors.forename: Jianing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Guangdong Provincial Engineering Research Center for Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
authors.forename: Yunping
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Allergy Center, Department of Otolaryngology-Head and Neck Surgery, Affiliated Eye and ENT Hospital, Fudan University, Shanghai 200031, China.|Guangdong Provincial Engineering Research Center for Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, China.
authors.forename: Huabin
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Pathology, Northwestern University Feinberg School of Medicine, 303 E Chicago Avenue, Chicago, Illinois 60611, USA.
authors.forename: Deyu
authors.initials: D
authors.lastname: Fang
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
chemical_list: C493961:Cdkn1b protein, mouse; D050760:Cyclin-Dependent Kinase Inhibitor p27; C482345:SYVN1 protein, human; C498235:Syvn1 protein, mouse; D044767:Ubiquitin-Protein Ligases