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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 \u03b2-selection is largely unknown. Here, we identify the endoplasmic reticulum (ER)-associated degradation (ERAD) machinery as a critical proteostasis checkpoint during \u03b2-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\n                    <jats:italic>Sel1l<\/jats:italic>\n                    impaired DN3 to DN4 thymocyte transition and severely impaired mouse \u03b1\u03b2 T cell development. Mechanistically,\n                    <jats:italic>Sel1l<\/jats:italic>\n                    deficiency induced unresolved ER stress that triggered thymocyte apoptosis through the PERK pathway. Accordingly, genetically inactivating PERK rescued T cell development from\n                    <jats:italic>Sel1l<\/jats:italic>\n                    -deficient thymocytes. In contrast, IRE1\u03b1\/XBP1 pathway was induced as a compensatory adaptation to alleviate\n                    <jats:italic>Sel1l<\/jats:italic>\n                    -deficiency-induced ER stress. Dual loss of\n                    <jats:italic>Sel1l<\/jats:italic>\n                    and\n                    <jats:italic>Xbp1<\/jats:italic>\n                    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.\n                  <\/jats:p>","DOI":"10.7554\/elife.69975","type":"journal-article","created":{"date-parts":[[2021,7,9]],"date-time":"2021-07-09T08:00:49Z","timestamp":1625817649000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.69975","source":"Crossref","is-referenced-by-count":35,"title":["Notch-induced endoplasmic reticulum-associated degradation governs mouse thymocyte \u03b2\u2212selection"],"prefix":"10.7554","volume":"10","author":[{"given":"Xia","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States"},{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2408-5809","authenticated-orcid":true,"given":"Jingjing","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States"},{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8574-4062","authenticated-orcid":true,"given":"Longyong","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States"},{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6416-0466","authenticated-orcid":true,"given":"Katharine","family":"Umphred-Wilson","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanglue","family":"Peng","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States"},{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yao","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States"},{"name":"Lester and Sue Smith Breast Center and Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan M","family":"Barton","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangdong","family":"Lv","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Y","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengyi","family":"Sun","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine and Genetics, Wayne State University, Detroit, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuning","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Physics, La Trobe University, Melbourne, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley","family":"Adoro","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7995-6202","authenticated-orcid":true,"given":"Xi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, 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