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Notch-induced endoplasmic reticulum-associated degradation governs mouse thymocyte beta-selection

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journal contribution
posted on 2021-08-20, 01:25 authored by Xia Liu, Jingjing Yu, Longyong Xu, Katharine Umphred-Wilson, Fanglue Peng, Yao Ding, Brendan M Barton, Xiangdong Lv, Michael Y Zhao, Shengyi Sun, Yuning HongYuning Hong, Ling Qi, Stanley Adoro, Xi Chen
Signals from the pre-T cell receptor and Notch coordinately instruct β-selection of CD4–CD8–double negative (DN) thymocytes to generate αβ T cells in the thymus. However, how these signals ensure a high-fidelity proteome and safeguard the clonal diversification of the pre-selection TCR repertoire given the considerable translational activity imposed by β-selection is largely unknown. Here, we identify the endoplasmic reticulum (ER)-associated degradation (ERAD) machinery as a critical proteostasis checkpoint during β-selection. Expression of the SEL1L-HRD1 complex, the most conserved branch of ERAD, is directly regulated by the transcriptional activity of the Notch intracellular domain. Deletion of Sel1l impaired DN3 to DN4 thymocyte transition and severely impaired mouse αβ T cell development. Mechanistically, Sel1l deficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. Accordingly, genetically inactivating PERK rescued T cell development from Sel1l-deficient thymocytes. In contrast, IRE1α/XBP1 pathway was induced as a compensatory adaptation to alleviate Sel1l-deficiency-induced ER stress. Dual loss of Sel1l and Xbp1 markedly exacerbated the thymic defect. Our study reveals a critical developmental signal controlled proteostasis mechanism that enforces T cell development to ensure a healthy adaptive immunity.


National Heart, Lung, and Blood Institute R01HL146642 Xi Chen National Institute of Allergy and Infectious Diseases R01 AI1143992 Stanley Adoro National Cancer Institute R37CA228304 Xi Chen National Cancer Institute K22CA218467 Stanley Adoro National Cancer Institute P50CA186784 Xi Chen National Institute of General Medical Sciences R35GM130292 Ling Qi DOD Peer Reviewed Cancer Research Program W81XWH1910524 Xi Chen DOD Peer Reviewed Cancer W81XWH1910306 Stanley Adoro Zhao MY, Sun S, Hong Y, Qi L, Adoro S, Chen X


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