{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:07:14Z","timestamp":1790791634724,"version":"4.1.0"},"reference-count":34,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T00:00:00Z","timestamp":1744588800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["JP22H05188"],"award-info":[{"award-number":["JP22H05188"]}]},{"name":"JSPS KAKENHI","award":["JP22H05182"],"award-info":[{"award-number":["JP22H05182"]}]},{"name":"JST SPRING","award":["JPMJSP2113"],"award-info":[{"award-number":["JPMJSP2113"]}]},{"name":"COI-NEXT Support Unit for Imaging Science at Kento"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Proteasomes are essential molecular complexes that regulate intracellular protein homeostasis by selectively degrading ubiquitinated proteins. Genetic mutations in proteasome subunits lead to proteasome-associated autoinflammatory syndromes (PRAAS) characterized by autoinflammation, partial progressive lipodystrophy, and, in certain cases, immunodeficiency. However, the molecular mechanisms by which proteasome dysfunction results in these phenotypes remain unclear. Here, we established a mouse model carrying a mutation in \u03b25i (encoded by Psmb8) along with T-cell-specific \u03b25 (encoded by Psmb5) deficiency (KIKO mice). The KIKO mice presented severe loss of mature T cells in the spleen but not in the thymus, with reduced proteasome activity leading to the accumulation of ubiquitinated proteins. The CD4+ T cells of KIKO mice presented impaired proliferative activity with cell cycle arrest in the G0\/G1 phase following T cell receptor (TCR) engagement. T cells from KIKO mice underwent rapid cell death through apoptosis, as treatment of T cells with the caspase inhibitor Z-Val-Ala-Asp(Ome)-fluoromethylketone (Z-VAD-FMK) rescued cell viability. Moreover, proteasome dysfunction induced apoptosis in T cells without affecting either mitochondrial functions or endoplasmic reticulum (ER) stress responses. Thus, our data provide insight into the molecular mechanisms underlying not only immunodeficiency in PRAAS patients but also T-cell deficiency associated with other disorders.<\/jats:p>","DOI":"10.1093\/intimm\/dxaf021","type":"journal-article","created":{"date-parts":[[2025,4,14]],"date-time":"2025-04-14T04:52:21Z","timestamp":1744606341000},"page":"493-505","source":"Crossref","is-referenced-by-count":4,"title":["Proteasome dysfunction in T cells causes immunodeficiency via cell cycle disruption and apoptosis"],"prefix":"10.1093","volume":"37","author":[{"given":"Erkhembayar","family":"Shinebaatar","sequence":"first","affiliation":[{"name":"Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University , Tokushima 770-8503 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junko","family":"Morimoto","sequence":"additional","affiliation":[{"name":"Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University , Tokushima 770-8503 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rinna","family":"Koga","sequence":"additional","affiliation":[{"name":"Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University , Tokushima 770-8503 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thanh Nam","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University , Tokushima 770-8503 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University , Tokushima 770-8503 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shigenobu","family":"Yonemura","sequence":"additional","affiliation":[{"name":"Department of Cell Biology, Graduate School of Medicine, Tokushima University , Tokushima 770-8503 ,","place":["Japan"]},{"name":"Laboratory for Ultrastructural Research, RIKEN Center for Biosystems Dynamics Research , Hyogo 650-0047 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetaka","family":"Kosako","sequence":"additional","affiliation":[{"name":"Division of Cell Signaling, Fujii Memorial Institute for Medical Sciences, Institute of Advanced Medical Sciences, Tokushima University , Tokushima 770-8503 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koji","family":"Yasutomo","sequence":"additional","affiliation":[{"name":"Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University , Tokushima 770-8503 ,","place":["Japan"]},{"name":"Department of Interdisciplinary Research on Medicine and Photonics, Institute of Post-LED Photonics, Tokushima University , Tokushima 770-8503 ,","place":["Japan"]},{"name":"The Research Cluster Program on Immunological Diseases, Tokushima University , Tokushima, 770-8503 ,","place":["Japan"]},{"name":"Institute of Photonics and Human Health Frontier, Tokushima University , Tokushima 770-8503 ,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,4,14]]},"reference":[{"key":"2025072301414452200_CIT0001","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1038\/nri2687","article-title":"Proteasomes in immune cells: more than peptide producers","volume":"10","author":"Groettrup","year":"2010","journal-title":"Nat Rev Immunol"},{"key":"2025072301414452200_CIT0002","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1038\/s41590-018-0186-z","article-title":"The 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Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/intimm\/advance-article-pdf\/doi\/10.1093\/intimm\/dxaf021\/62924926\/dxaf021.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/intimm\/article-pdf\/37\/8\/493\/62924926\/dxaf021.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/intimm\/article-pdf\/37\/8\/493\/62924926\/dxaf021.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,23]],"date-time":"2025-07-23T05:41:53Z","timestamp":1753249313000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/intimm\/article\/37\/8\/493\/8113131"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,14]]},"references-count":34,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2025,4,14]]},"published-print":{"date-parts":[[2025,7,22]]}},"URL":"https:\/\/doi.org\/10.1093\/intimm\/dxaf021","relation":{},"ISSN":["1460-2377"],"issn-type":[{"value":"1460-2377","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,8]]},"published":{"date-parts":[[2025,4,14]]}}}