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Adv."],"published-print":{"date-parts":[[2026,8,21]]},"abstract":"<jats:p>\n                    T helper 17 (T\n                    <jats:sub>H<\/jats:sub>\n                    17) cells are heterogeneous and able to adopt pathogenic and non-pathogenic phenotypes. Identifying factors controlling pathogenic T\n                    <jats:sub>H<\/jats:sub>\n                    17 cells is of importance for their vital role in inflammation and immune-pathology. Here, we demonstrated that HMGCS1, a cholesterol biosynthesis precursor enzyme, was highly induced by inflammatory cytokines and preferentially expressed by pathogenic T\n                    <jats:sub>H<\/jats:sub>\n                    17 cells in vitro and in vivo. HMGCS1 specifically dictated pathogenic T\n                    <jats:sub>H<\/jats:sub>\n                    17 cell differentiation and augmented autoimmune diseases, yet it has no discernible effect on nonpathogenic T\n                    <jats:sub>H<\/jats:sub>\n                    17 cells. Unexpectedly, this role is independent of its canonical function in cholesterol metabolism but requires its catalytic Cys\n                    <jats:sup>129<\/jats:sup>\n                    residue. Notably, HMGCS1 governs pT\n                    <jats:sub>H<\/jats:sub>\n                    17 cell generation and pathogenicity by leveraging an IRE1\u03b1-XBP1s\u2013dependent ER stress response, which in turn transcriptionally activates the lineage-defining factor ROR\u03b3t (encoded by\n                    <jats:italic toggle=\"yes\">Rorc<\/jats:italic>\n                    ). Mechanistically, HMGCS1 is located to the ER membrane, where it bound and stabilized IRE1\u03b1 protein. This stabilization is achieved by preventing IRE1\u03b1\u2019s interaction with the E3 ubiquitin ligase MARCH5, thereby inhibiting its K48-linked ubiquitination and subsequent degradation. Moreover, interfering with HMGCS1 or the ER stress response in T cells impedes pT\n                    <jats:sub>H<\/jats:sub>\n                    17 immunity and mitigates autoimmune disease in vivo. Therefore, our work unveils a noncanonical axis in which HMGCS1 sustains ER stress to license pT\n                    <jats:sub>H<\/jats:sub>\n                    17 differentiation during autoimmune responses.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aee4337","type":"journal-article","created":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:59:26Z","timestamp":1787162366000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Unconventional role of hydroxymethylglutaryl-CoA synthase 1 in driving pathogenic T\n                    <sub>H<\/sub>\n                    17 cell immunity and autoimmune diseases"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-0207-9601","authenticated-orcid":true,"given":"Jie","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Urology, State Key Laboratory of Virology and Biosafety, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China."},{"name":"Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-0393-2595","authenticated-orcid":true,"given":"Yali","family":"Lei","sequence":"additional","affiliation":[{"name":"Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0827-991X","authenticated-orcid":true,"given":"Huanhuan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Urology, State Key Laboratory of Virology and Biosafety, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China."},{"name":"Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0007-5198","authenticated-orcid":true,"given":"Shu","family":"Li","sequence":"additional","affiliation":[{"name":"Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1656-3783","authenticated-orcid":true,"given":"Bing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Urology, State Key Laboratory of Virology and Biosafety, Medical Research Institute, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China."},{"name":"Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430071, 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