Notch-induced endoplasmic reticulum-associated degradation governs mouse thymocyte β−selection
Abstract
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 09, 2021
- Source ID
- 10.7554/elife.69975
Entities
People
- Brendan M Barton
- Fanglue Peng
- Jingjing Yu
- Katharine Umphred-Wilson
- Ling Qi
- Longyong Xu
- Michael Y Zhao
- Shengyi Sun
- Stanley Adoro
- Xi Chen
- Xia Liu
- Xiangdong Lv
- Yao Ding
- Yuning Hong
Organizations
- Baylor College of Medicine
- Cancer Prevention and Research Institute of Texas
- Case Western Reserve University
- Congressionally Directed Medical Research Programs
- La Trobe University
- National Cancer Institute
- National Heart, Lung, and Blood Institute
- National Institute of Allergy and Infectious Diseases
- National Institute of General Medical Sciences
- University of Michigan
- Wayne State University