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

Yuanming Xu, Fang Zhao, Quan Qiu, Kun Chen, Juncheng Wei, Qingfei Kong, Beixue Gao, Johanna Melo-Cardenas, Bin Zhang, Jinping Zhang, Jianxun Song, Donna D. Zhang, Jianing Zhang, Yunping Fan, Huabin Li () and Deyu Fang ()
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Yuanming Xu: Northwestern University Feinberg School of Medicine
Fang Zhao: Northwestern University Feinberg School of Medicine
Quan Qiu: Northwestern University Feinberg School of Medicine
Kun Chen: Allergy Center, Affiliated Eye and ENT Hospital, Fudan University
Juncheng Wei: Northwestern University Feinberg School of Medicine
Qingfei Kong: Northwestern University Feinberg School of Medicine
Beixue Gao: Northwestern University Feinberg School of Medicine
Johanna Melo-Cardenas: Northwestern University Feinberg School of Medicine
Bin Zhang: Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine
Jinping Zhang: Institutes of Biology and Medical Sciences, Soochow University
Jianxun Song: The Pennsylvania State University College of Medicine
Donna D. Zhang: College of Pharmacy, University of Arizona
Jianing Zhang: School of Life Science and Medicine, Dalian University of Technology
Yunping Fan: Guangdong Provincial Engineering Research Center for Molecular Imaging, The Fifth Affiliated Hospital, Sun Yat-sen University
Huabin Li: Allergy Center, Affiliated Eye and ENT Hospital, Fudan University
Deyu Fang: Northwestern University Feinberg School of Medicine

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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 p27kip1, and deletion of p27kip1 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.

Date: 2016
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DOI: 10.1038/ncomms12073

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