{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T07:48:43Z","timestamp":1792568923254,"version":"4.5.0"},"reference-count":60,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2024,9,12]],"date-time":"2024-09-12T00:00:00Z","timestamp":1726099200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kishimoto Foundation","award":["J218501011"],"award-info":[{"award-number":["J218501011"]}]},{"name":"Kishimoto Foundation","award":["69"],"award-info":[{"award-number":["69"]}]},{"name":"the Advanced Postdoc Program, IFReC, Osaka University","award":["J218501011"],"award-info":[{"award-number":["J218501011"]}]},{"name":"the Advanced Postdoc Program, IFReC, Osaka University","award":["69"],"award-info":[{"award-number":["69"]}]},{"name":"CHUGAI pharmaceuticals","award":["J218501011"],"award-info":[{"award-number":["J218501011"]}]},{"name":"CHUGAI pharmaceuticals","award":["69"],"award-info":[{"award-number":["69"]}]},{"name":"Ministry of Higher Education of the Arab Republic of Egypt","award":["J218501011"],"award-info":[{"award-number":["J218501011"]}]},{"name":"Ministry of Higher Education of the Arab Republic of Egypt","award":["69"],"award-info":[{"award-number":["69"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Threonine phosphorylation promotes inflammatory functions of STAT1 while restricting its interferon (IFN) signaling in innate immune responses. However, it remains unclear whether the restriction of STAT1-mediated IFN signaling conferred by threonine phosphorylation is a ubiquitous mechanism or one that is context-dependent. To address this, we utilized pristane-induced lupus, a prototype IFN-driven systemic autoimmune disease model characterized by the production of high-titer autoantibodies against nucleic acid-associated antigens. Through genetic and biochemical assays, we demonstrate that Thr748 phosphorylation is dispensable for STAT1 functionality in pristane-induced lupus. Genetically engineered mice expressing the phospho-deficient threonine 748-to-alanine (T748A) mutant STAT1 exhibited similar survival rates, high titers of anti-dsDNA IgG, and nephritis compared to their wild-type littermates. In sharp contrast, STAT1 deficiency protected mice against pristane-induced lupus, as evidenced by increased survival, low titers of anti-dsDNA IgG, and less severe nephritis in the STAT1 knockout mice compared to their T748A littermates. Our study suggests a phosphorylation-dependent modularity that governs the spectrum of STAT1 functionality in inflammatory contexts: IFN phospho-tyrosine-dependent and inflammatory phospho-threonine-dependent, with Thr748 phosphorylation driving selective inflammatory activities, particularly those not driven by the canonical JAK pathway. From a broader perspective, our findings provide deeper insights into how distinct phosphorylation events shape the combinatorial logic of signaling cassettes, thereby regulating context-dependent responses.<\/jats:p>","DOI":"10.3390\/cells13181531","type":"journal-article","created":{"date-parts":[[2024,9,12]],"date-time":"2024-09-12T06:31:40Z","timestamp":1726122700000},"page":"1531","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Threonine Phosphorylation and the Yin and Yang of STAT1: Phosphorylation-Dependent Spectrum of STAT1 Functionality in Inflammatory Contexts"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3167-8653","authenticated-orcid":false,"given":"Maha M.","family":"Elbrashy","sequence":"first","affiliation":[{"name":"Laboratory of Immune Regulation, Immunology Frontier Research Center, The World Premier International Research Center Initiative (WPI), Osaka University, Osaka 565-0871, Japan"},{"name":"Biochemistry Department, Biotechnology Research Institute, National Research Center, Giza P.O. Box 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8664-096X","authenticated-orcid":false,"given":"Hozaifa","family":"Metwally","sequence":"additional","affiliation":[{"name":"Laboratory of Immune Regulation, Immunology Frontier Research Center, The World Premier International Research Center Initiative (WPI), Osaka University, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3157-5870","authenticated-orcid":false,"given":"Shuhei","family":"Sakakibara","sequence":"additional","affiliation":[{"name":"Laboratory of Immune Regulation, Immunology Frontier Research Center, The World Premier International Research Center Initiative (WPI), Osaka University, Osaka 565-0871, Japan"},{"name":"Graduate School of Medical Safety Management, Jikei University of Health Care Sciences, Osaka 532-0003, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadamitsu","family":"Kishimoto","sequence":"additional","affiliation":[{"name":"Laboratory of Immune Regulation, Immunology Frontier Research Center, The World Premier International Research Center Initiative (WPI), Osaka University, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,9,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7342","DOI":"10.1002\/anie.200501023","article-title":"Protein Posttranslational Modifications: The Chemistry of Proteome Diversifications","volume":"44","author":"Walsh","year":"2005","journal-title":"Angew. 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