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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: The ER membrane-anchored ubiquitin ligase Hrd1 is a positive regulator of T-cell immunity.

Authors: Xu, Yuanming; Zhao, Fang; Qiu, Quan; Chen, Kun; Wei, Juncheng; Kong, Qingfei; Gao, Beixue; Melo-Cardenas, Johanna; Zhang, Bin; Zhang, Jinping; Song, Jianxun; Zhang, Donna D; Zhang, Jianing; Fan, Yunping; Li, Huabin; Fang, Deyu

Published In Nat Commun, (2016 07 15)

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.

PubMed ID: 27417417 Exiting the NIEHS site

MeSH Terms: Animals; CD4-Positive T-Lymphocytes/immunology; Cyclin-Dependent Kinase Inhibitor p27/metabolism; Encephalomyelitis, Autoimmune, Experimental/immunology; Endoplasmic Reticulum/metabolism*; Humans; Intracellular Membranes/metabolism; Lymphocyte Activation/immunology; Mice, Knockout; Mice, Transgenic; Multiple Sclerosis/immunology; T-Lymphocytes/immunology*; T-Lymphocytes/metabolism; Th1 Cells/immunology; Th17 Cells/immunology; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/immunology*; Ubiquitin-Protein Ligases/metabolism*

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