Nature Communications (May 2023)

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

  • Xiangling Xiao,
  • Jie Shi,
  • Chuan He,
  • Xia Bu,
  • Yishuang Sun,
  • Minling Gao,
  • Bolin Xiang,
  • Wenjun Xiong,
  • Panpan Dai,
  • Qi Mao,
  • Xixin Xing,
  • Yingmeng Yao,
  • Haisheng Yu,
  • Gaoshan Xu,
  • Siqi Li,
  • Yan Ren,
  • Baoxiang Chen,
  • Congqing Jiang,
  • Geng Meng,
  • Yu-Ru Lee,
  • Wenyi Wei,
  • Gordon J. Freeman,
  • Conghua Xie,
  • Jinfang Zhang

DOI
https://doi.org/10.1038/s41467-023-38605-3
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 19

Abstract

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Abstract 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.