ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy

Nat Commun. 2023 May 19;14(1):2859. doi: 10.1038/s41467-023-38605-3.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Extracellular Signal-Regulated MAP Kinases*
  • Homeostasis
  • Immunotherapy
  • Mice
  • Programmed Cell Death 1 Receptor*
  • Ubiquitin-Specific Proteases / genetics
  • Ubiquitin-Specific Proteases / metabolism


  • Extracellular Signal-Regulated MAP Kinases
  • Programmed Cell Death 1 Receptor
  • Ubiquitin-Specific Proteases
  • Usp5 protein, mouse