{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T21:11:38Z","timestamp":1792617098126,"version":"4.5.0"},"reference-count":48,"publisher":"National Academy of Sciences","issue":"17","license":[{"start":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T00:00:00Z","timestamp":1713139200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,4,23]]},"abstract":"<jats:p>\n                    Since its discovery over three decades ago, signal transducer and activator of transcription 1 (STAT1) has been extensively studied as a central mediator for interferons (IFNs) signaling and antiviral defense. Here, using genetic and biochemical assays, we unveil Thr\n                    <jats:sup>748<\/jats:sup>\n                    as a conserved IFN-independent phosphorylation switch in Stat1, which restricts IFN signaling and promotes innate inflammatory responses following the recognition of the bacterial-derived toxin lipopolysaccharide (LPS). Genetically engineered mice expressing phospho-deficient threonine748-to-alanine (T748A) mutant Stat1 are resistant to LPS-induced lethality. Of note, T748A mice exhibited undisturbed IFN signaling, as well as total expression of Stat1. Further, the T748A point mutation of Stat1 recapitulates the safeguard effect of the genetic ablation of\n                    <jats:italic>Stat1<\/jats:italic>\n                    following LPS-induced lethality, indicating that the Thr\n                    <jats:sup>748<\/jats:sup>\n                    phosphorylation contributes inflammatory functionalities of Stat1. Mechanistically, LPS-induced Toll-like receptor 4 endocytosis activates a cell-intrinsic I\u03baB kinase-mediated Thr\n                    <jats:sup>748<\/jats:sup>\n                    phosphorylation of Stat1, which promotes macrophage inflammatory response while restricting the IFN and anti-inflammatory responses. Depletion of macrophages restores the sensitivity of the T748A mice to LPS-induced lethality. Together, our study indicates a phosphorylation-dependent modular functionality of Stat1 in innate immune responses: IFN phospho-tyrosine dependent and inflammatory phospho-threonine dependent. Better understanding of the Thr\n                    <jats:sup>748<\/jats:sup>\n                    phosphorylation of Stat1 may uncover advanced pharmacologically targetable molecules and offer better treatment modalities for sepsis, a disease that claims millions of lives annually.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2402226121","type":"journal-article","created":{"date-parts":[[2024,4,15]],"date-time":"2024-04-15T15:06:53Z","timestamp":1713193613000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":29,"title":["Threonine phosphorylation of STAT1 restricts interferon signaling and promotes innate inflammatory responses"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8664-096X","authenticated-orcid":false,"given":"Hozaifa","family":"Metwally","sequence":"first","affiliation":[{"name":"Laboratory of Immune Regulation, The World Premier International Research Center Initiative, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maha M.","family":"Elbrashy","sequence":"additional","affiliation":[{"name":"Laboratory of Immune Regulation, The World Premier International Research Center Initiative, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan"},{"name":"Biochemistry Department, Biotechnology Research Institute, National Research Center, Giza P.O. 12622, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3112-452X","authenticated-orcid":false,"given":"Tatsuhiko","family":"Ozawa","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama 930-0194, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Okuyama","sequence":"additional","affiliation":[{"name":"Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Tsurumi-ku, Yokohama, Kanagawa 230-0045, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason T.","family":"White","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Immunology, The World Premier International Research Center Initiative, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1473-5561","authenticated-orcid":false,"given":"Janyerkye","family":"Tulyeu","sequence":"additional","affiliation":[{"name":"Human Immunology Team, Center for Infectious Disease Education and Research, Osaka University, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4438-6756","authenticated-orcid":false,"given":"Jonas N\u00f8rskov","family":"S\u00f8ndergaard","sequence":"additional","affiliation":[{"name":"Human Immunology Team, Center for Infectious Disease Education and Research, Osaka University, Suita 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3462-1003","authenticated-orcid":false,"given":"James Badger","family":"Wing","sequence":"additional","affiliation":[{"name":"Laboratory of Human Single Cell Immunology, The World Premier International Research Center Initiative, Immunology Frontier Research Center, Osaka University, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arisa","family":"Muratsu","sequence":"additional","affiliation":[{"name":"Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisatake","family":"Matsumoto","sequence":"additional","affiliation":[{"name":"Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9859-6217","authenticated-orcid":false,"given":"Masahito","family":"Ikawa","sequence":"additional","affiliation":[{"name":"Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8740-5371","authenticated-orcid":false,"given":"Hiroyuki","family":"Kishi","sequence":"additional","affiliation":[{"name":"Department of Immunology, Faculty of Medicine, Academic Assembly, University of Toyama, Toyama 930-0194, 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