SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 + T cells.

Autor:	Celada SI; Department of Biological Sciences, Tennessee State University, Nashville, TN 37209, USA., Lim CX; Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna 1090, Austria., Carisey AF; William T. Shearer Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA.; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Cell and Molecular Biology, St. Jude Children's Hospital, Memphis, TN 38105, USA., Ochsner SA; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA., Arce Deza CF; Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA., Rexie P; Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna 1090, Austria., Poli De Frias F; Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA.; Mount Sinai Medical Center, Miami Beach, FL 33140, USA., Cardenas-Castillo R; Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA., Polverino F; Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA., Hengstschläger M; Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna 1090, Austria., Tsoyi K; Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA., McKenna NJ; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA., Kheradmand F; Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA.; Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA., Weichhart T; Center of Pathobiochemistry and Genetics, Institute of Medical Genetics, Medical University of Vienna, Vienna 1090, Austria., Rosas IO; Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA., Van Kaer L; Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA., Celada LJ; Department of Medicine, Section of Pulmonary, Critical Care and Sleep Medicine, Baylor College of Medicine, Houston, TX 77030, USA.; Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2023 Sep 13; Vol. 15 (713), pp. eade2581. Date of Electronic Publication: 2023 Sep 13.
DOI:	10.1126/scitranslmed.ade2581
Abstrakt:	Sarcoidosis is an interstitial lung disease (ILD) characterized by interferon-γ (IFN-γ) 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-γ 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 + T cells. Mechanistically, we identified a posttranslational modification pathway in which the E3 F-box protein S-phase kinase-associated protein 2 (SKP2) targets TBET for ubiquitination in T cells under normal conditions. However, this pathway was disrupted by aberrant pSHP2 signaling in CD8 + T cells from patients with progressive pulmonary sarcoidosis and end-stage disease. Ex vivo inhibition of pSHP2 in CD8 + T cells from patients with end-stage sarcoidosis enhanced TBET ubiquitination and suppressed IFN-γ 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.
Databáze:	MEDLINE
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