{"doi":"10.1126/scitranslmed.ade2581","title":"SHP2 promotes sarcoidosis severity by inhibiting SKP2-targeted ubiquitination of TBET in CD8 <sup>+</sup> T cells","abstract":"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.","journal":"Science Translational Medicine","year":2023,"id":353004,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9598,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1098867,"name":"Clarice X. Lim","orcid":"0000-0001-7297-0055","position":1,"is_corresponding":false},{"id":245874,"name":"Alexandre F. Carisey","orcid":"0000-0003-1326-2205","position":2,"is_corresponding":false},{"id":944338,"name":"Scott A. Ochsner","orcid":"0000-0003-1099-7863","position":3,"is_corresponding":false},{"id":1099243,"name":"Carlos F. Arce Deza","orcid":null,"position":4,"is_corresponding":false},{"id":1098868,"name":"Praveen Rexie","orcid":"0000-0001-6388-6716","position":5,"is_corresponding":false},{"id":826214,"name":"Fernando Poli de Frias","orcid":"0000-0003-0022-6694","position":6,"is_corresponding":false},{"id":1098869,"name":"Rafael Cardenas-Castillo","orcid":"0000-0003-2749-3565","position":7,"is_corresponding":false},{"id":232045,"name":"Francesca Polverino","orcid":"0000-0001-9686-5698","position":8,"is_corresponding":false},{"id":1098870,"name":"Markus Hengstschläger","orcid":"0000-0002-3342-7583","position":9,"is_corresponding":false},{"id":731757,"name":"Konstantin Tsoyi","orcid":"0000-0001-5843-5427","position":10,"is_corresponding":false},{"id":64666,"name":"Neil J. McKenna","orcid":"0000-0001-6689-0104","position":11,"is_corresponding":false},{"id":232202,"name":"Farrah Kheradmand","orcid":"0000-0001-5343-103X","position":12,"is_corresponding":false},{"id":1098871,"name":"Thomas Weichhart","orcid":"0000-0002-4349-0797","position":13,"is_corresponding":false},{"id":34736,"name":"Iván O. Rosas","orcid":"0000-0003-4622-618X","position":14,"is_corresponding":false},{"id":302765,"name":"Luc Van Kaer","orcid":"0000-0001-5275-2309","position":15,"is_corresponding":false},{"id":912216,"name":"Lindsay J. Celada","orcid":"0000-0002-8462-136X","position":16,"is_corresponding":false},{"id":329327,"name":"Sherly I. Celada","orcid":"0009-0004-7064-1855","position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":null,"created_at":"2026-07-19T01:12:54.209378Z","pmid":"37703351","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}