SHP2 Promotes Sarcoidosis Severity by Inhibiting SKP2-Targeted Ubiquitination of TBET in CD8+ T cells

Authors

Sherly I Celada
Clarice X Lim
Alexandre F Carisey
Scott A Ochsner
Carlos F Arce Deza
Praveen Rexie
Fernando Poli De Frias
Rafael Cardenas-Castillo
Francesca Polverino
Markus Hengstschläger
Konstantin Tsoyi
Neil J McKenna
Farrah Kheradmand
Thomas Weichhart
Ivan O Rosas
Luc Van Kaer
Lindsay J Celada

Publication Date

9-13-2023

Journal

Science Translational Medicine

DOI

10.1126/scitranslmed.ade2581

PMID

37703351

PMCID

PMC11126869

PubMedCentral® Posted Date

9-13-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Humans, Animals, Mice, CD8-Positive T-Lymphocytes, Sarcoidosis, Ubiquitination, Protein Processing, Post-Translational, Interferon-gamma, sarcoidosis, E3 ubiquitin ligase, SHP2, TBET, SKP2, IFNγ

Abstract

Sarcoidosis is an interstitial lung disease (ILD) characterized by IFNγ and 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 report that pharmacological inhibition of phosphorylated SH2 containing protein tyrosine phosphatase-2 (pSHP2), a facilitator of aberrant IFNγ levels, decreases 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, our findings identified a previously unknown post-translational modification (PTM) 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 as well as end-stage disease. Ex vivo inhibition of pSHP2 in CD8+ T cells from end-stage sarcoidosis patients enhanced TBET ubiquitination while suppressing IFNγ and collagen synthesis. Therefore, our functional data provide new mechanistic insights into the SHP2-dependent post-translational regulation of TBET and identify SHP2 inhibition as a potential therapeutic intervention against severe sarcoidosis. Broadly, this study also implicates the possibility of using SHP099 as a therapeutic measure against human diseases linked to TBET or ubiquitination.

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