ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
Dokumenter
- Fulltext
Forlagets udgivne version, 3,31 MB, PDF-dokument
The programmed cell death protein 1 (PD-1) is an inhibitory receptor on T cells and plays an important role in promoting cancer immune evasion. While ubiquitin E3 ligases regulating PD-1 stability have been reported, deubiquitinases governing PD-1 homeostasis to modulate tumor immunotherapy remain unknown. Here, we identify the ubiquitin-specific protease 5 (USP5) as a bona fide deubiquitinase for PD-1. Mechanistically, USP5 interacts with PD-1, leading to deubiquitination and stabilization of PD-1. Moreover, extracellular signal-regulated kinase (ERK) phosphorylates PD-1 at Thr234 and promotes PD-1 interaction with USP5. Conditional knockout of Usp5 in T cells increases the production of effector cytokines and retards tumor growth in mice. USP5 inhibition in combination with Trametinib or anti-CTLA-4 has an additive effect on suppressing tumor growth in mice. Together, this study describes a molecular mechanism of ERK/USP5-mediated regulation of PD-1 and identifies potential combinatorial therapeutic strategies for enhancing anti-tumor efficacy.
Originalsprog | Engelsk |
---|---|
Artikelnummer | 2859 |
Tidsskrift | Nature Communications |
Vol/bind | 14 |
Udgave nummer | 1 |
Antal sider | 19 |
ISSN | 2041-1723 |
DOI | |
Status | Udgivet - 2023 |
Bibliografisk note
Publisher Copyright:
© 2023. The Author(s).
ID: 347804915