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Decreased proteasome activity is associated with the aging process; however, the regulation of the proteasome in CD4<jats:sup>+<\/jats:sup> T cells in relation to aging is unclear. Here, we show that defects in the induction of the proteasome in CD4<jats:sup>+<\/jats:sup> T cells upon T\u2010cell receptor (TCR) stimulation underlie T\u2010cell senescence. Proteasome dysfunction promotes senescence\u2010associated phenotypes, including defective proliferation, cytokine production and increased levels of PD\u20101<jats:sup>+<\/jats:sup> CD44<jats:sup>High<\/jats:sup> CD4<jats:sup>+<\/jats:sup> T cells. Proteasome induction by TCR signaling via MEK\u2010, IKK\u2010 and calcineurin\u2010dependent pathways is attenuated with age and decreased in PD\u20101<jats:sup>+<\/jats:sup> CD44<jats:sup>High<\/jats:sup> CD4<jats:sup>+<\/jats:sup> T cells, the proportion of which increases with age. Our results indicate that defective induction of the proteasome is a hallmark of CD4<jats:sup>+<\/jats:sup> T\u2010cell senescence.<\/jats:p>","DOI":"10.1111\/gtc.12728","type":"journal-article","created":{"date-parts":[[2019,10,17]],"date-time":"2019-10-17T07:28:36Z","timestamp":1571297316000},"page":"801-813","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Defective induction of the proteasome associated with T\u2010cell receptor signaling underlies T\u2010cell senescence"],"prefix":"10.1111","volume":"24","author":[{"given":"Yoshiyuki","family":"Arata","sequence":"first","affiliation":[{"name":"Laboratory of Protein Metabolism Graduate School of Pharmaceutical Sciences The University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayaka","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Metabolism Graduate School of Pharmaceutical Sciences The University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryo","family":"Motosugi","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Metabolism Graduate School of Pharmaceutical Sciences The University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryuichi","family":"Murakami","sequence":"additional","affiliation":[{"name":"Laboratory of Immunology and Microbiology Graduate School of Pharmaceutical Sciences The University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsuyoshi","family":"Goto","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Metabolism Graduate School of Pharmaceutical Sciences The University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shohei","family":"Hori","sequence":"additional","affiliation":[{"name":"Laboratory of Immunology and Microbiology Graduate School of Pharmaceutical Sciences The University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shoshiro","family":"Hirayama","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Metabolism Graduate School of Pharmaceutical Sciences The University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Hamazaki","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Metabolism Graduate School of Pharmaceutical Sciences The University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3177-3503","authenticated-orcid":false,"given":"Shigeo","family":"Murata","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Metabolism Graduate School of Pharmaceutical Sciences The University of Tokyo Tokyo Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2019,11,6]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(04)00120-5"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1106015108"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80929-0"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2007.02761.x"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-015-0486-4"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI81260"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1600827"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.coi.2012.04.003"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.bi.65.070196.004101"},{"issue":"12","key":"e_1_2_7_11_1","first-page":"5","article-title":"T cell receptor signal transduction in T lymphocytes","volume":"2012","author":"Gorentla B. 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