ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy
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ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy. / Xiao, Xiangling; Shi, Jie; He, Chuan; Bu, Xia; Sun, Yishuang; Gao, Minling; Xiang, Bolin; Xiong, Wenjun; Dai, Panpan; Mao, Qi; Xing, Xixin; Yao, Yingmeng; Yu, Haisheng; Xu, Gaoshan; Li, Siqi; Ren, Yan; Chen, Baoxiang; Jiang, Congqing; Meng, Geng; Lee, Yu Ru; Wei, Wenyi; Freeman, Gordon J.; Xie, Conghua; Zhang, Jinfang.
I: Nature Communications, Bind 14, Nr. 1, 2859, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - ERK and USP5 govern PD-1 homeostasis via deubiquitination to modulate tumor immunotherapy
AU - Xiao, Xiangling
AU - Shi, Jie
AU - He, Chuan
AU - Bu, Xia
AU - Sun, Yishuang
AU - Gao, Minling
AU - Xiang, Bolin
AU - Xiong, Wenjun
AU - Dai, Panpan
AU - Mao, Qi
AU - Xing, Xixin
AU - Yao, Yingmeng
AU - Yu, Haisheng
AU - Xu, Gaoshan
AU - Li, Siqi
AU - Ren, Yan
AU - Chen, Baoxiang
AU - Jiang, Congqing
AU - Meng, Geng
AU - Lee, Yu Ru
AU - Wei, Wenyi
AU - Freeman, Gordon J.
AU - Xie, Conghua
AU - Zhang, Jinfang
N1 - Publisher Copyright: © 2023. The Author(s).
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-023-38605-3
DO - 10.1038/s41467-023-38605-3
M3 - Journal article
C2 - 37208329
AN - SCOPUS:85159671957
VL - 14
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 2859
ER -
ID: 347804915