{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:45:30Z","timestamp":1790095530510,"version":"4.0.1"},"reference-count":81,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"713","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2023,9,13]]},"abstract":"<jats:p>\n            Sarcoidosis is an interstitial lung disease (ILD) characterized by interferon-\u03b3 (IFN-\u03b3) and T-box expressed in T cells (TBET) dysregulation. Although one-third of patients progress from granulomatous inflammation to severe lung damage, the molecular mechanisms underlying this process remain unclear. Here, we found that pharmacological inhibition of phosphorylated SH2-containing protein tyrosine phosphatase-2 (pSHP2), a facilitator of aberrant IFN-\u03b3 abundance, decreased large granuloma formation and macrophage infiltration in the lungs of mice with sarcoidosis-like disease. Positive treatment outcomes were dependent on the effective enhancement of TBET ubiquitination within CD8\n            <jats:sup>+<\/jats:sup>\n            T cells. Mechanistically, we identified a posttranslational modification pathway in which the E3 F-box protein S-phase kinase\u2013associated protein 2 (SKP2) targets TBET for ubiquitination in T cells under normal conditions. However, this pathway was disrupted by aberrant pSHP2 signaling in CD8\n            <jats:sup>+<\/jats:sup>\n            T cells from patients with progressive pulmonary sarcoidosis and end-stage disease. Ex vivo inhibition of pSHP2 in CD8\n            <jats:sup>+<\/jats:sup>\n            T cells from patients with end-stage sarcoidosis enhanced TBET ubiquitination and suppressed IFN-\u03b3 and collagen synthesis. Therefore, these studies provided new mechanistic insights into the SHP2-dependent posttranslational regulation of TBET and identified SHP2 inhibition as a potential therapeutic intervention against severe sarcoidosis. Furthermore, these studies also suggest that the small-molecule SHP2 inhibitor SHP099 might be used as a therapeutic measure against human diseases linked to TBET or ubiquitination.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.ade2581","type":"journal-article","created":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T17:58:39Z","timestamp":1694627919000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":8,"title":["SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8\n            <sup>+<\/sup>\n            T cells"],"prefix":"10.1126","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-7064-1855","authenticated-orcid":true,"given":"Sherly I.","family":"Celada","sequence":"first","affiliation":[{"name":"Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7297-0055","authenticated-orcid":true,"given":"Clarice X.","family":"Lim","sequence":"additional","affiliation":[{"name":"Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna 1090, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1326-2205","authenticated-orcid":true,"given":"Alexandre F.","family":"Carisey","sequence":"additional","affiliation":[{"name":"William T. Shearer Center for Human Immunobiology, Texas Children\u2019s Hospital, Houston, TX 77030, USA."},{"name":"Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Department of Cell and Molecular Biology, St. Jude Children\u2019s Hospital, Memphis, TN 38105, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1099-7863","authenticated-orcid":true,"given":"Scott A.","family":"Ochsner","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos F.","family":"Arce Deza","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6388-6716","authenticated-orcid":true,"given":"Praveen","family":"Rexie","sequence":"additional","affiliation":[{"name":"Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna 1090, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fernando","family":"Poli De Frias","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Mount Sinai Medical Center, Miami Beach, FL 33140, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2749-3565","authenticated-orcid":true,"given":"Rafael","family":"Cardenas-Castillo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Polverino","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Markus","family":"Hengstschl\u00e4ger","sequence":"additional","affiliation":[{"name":"Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna 1090, Austria."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantin","family":"Tsoyi","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6689-0104","authenticated-orcid":true,"given":"Neil J.","family":"McKenna","sequence":"additional","affiliation":[{"name":"Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5343-103X","authenticated-orcid":true,"given":"Farrah","family":"Kheradmand","sequence":"additional","affiliation":[{"name":"Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA."},{"name":"Center for Translational Research on Inflammatory Diseases, Michael E. 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