SENP7 senses oxidative stress to sustain metabolic fitness and antitumor functions of CD8+ T cells
Zhongqiu Wu, … , Zhengting Wang, Qiang Zou
Zhongqiu Wu, … , Zhengting Wang, Qiang Zou
Published February 10, 2022
Citation Information: J Clin Invest. 2022;132(7):e155224. https://doi.org/10.1172/JCI155224.
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Research Article Immunology Metabolism

SENP7 senses oxidative stress to sustain metabolic fitness and antitumor functions of CD8+ T cells

Abstract

The functional integrity of CD8+ T cells is tightly coupled to metabolic reprogramming, but how oxidative stress directs CD8+ T cell metabolic fitness in the tumor microenvironment (TME) remains elusive. Here, we report that SUMO-specific protease 7 (SENP7) senses oxidative stress to maintain the CD8+ T cell metabolic state and antitumor functions. SENP7-deficient CD8+ T cells exhibited decreased glycolysis and oxidative phosphorylation, resulting in attenuated proliferation in vitro and dampened antitumor functions in vivo. Mechanistically, CD8+ T cell–derived ROS triggered cytosolic SENP7–mediated PTEN deSUMOylation, thereby promoting PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, lowering T cell–intrinsic ROS restricted SENP7 cytosolic translocation and repressed CD8+ T cell metabolic and functional activity in human colorectal cancer samples. Our findings reveal that SENP7, as an oxidative stress sensor, sustains CD8+ T cell metabolic fitness and effector functions and unveil an oxidative stress–sensing machinery in tumor-infiltrating CD8+ T cells.

Authors

Zhongqiu Wu, Haiyan Huang, Qiaoqiao Han, Zhilin Hu, Xiao-Lu Teng, Rui Ding, Youqiong Ye, Xiaoyan Yu, Ren Zhao, Zhengting Wang, Qiang Zou

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Figure 6

SENP7-mediated PTEN deSUMOylation facilitates PTEN degradation.

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SENP7-mediated PTEN deSUMOylation facilitates PTEN degradation. (A) HEK2...
(A) HEK293T cells cotransfected with Flag-tagged PTEN, Ubc9, and RH-SUMO3 in the presence of WT or catalytically inactive (C979S) mutant (M) SENP7 were immunoprecipitated with anti-Flag antibody and assessed by immunoblotting (IB) with anti-SUMO2/3. HA, hemagglutinin; RH, arginine(R)-glycine(G)-serine(S)-histidine. (B) PTEN SUMOylation assays were performed by immunoprecipitating PTEN under denaturing conditions followed by detection of SUMOylated PTEN using anti-SUMO2/3 antibodies in CD8+ T cells stimulated with anti-CD3 and anti-CD28 antibodies. (C) Quantifications of PTEN-SUMO2/3:PTEN levels in CD8+ T cells stimulated with anti-CD3 and anti-CD28 antibodies (n = 3). (D) Immunoblot analysis of the indicated proteins in CD8+ T cells stimulated with anti-CD3 and anti-CD28 antibodies for 1 hour following incubation with CHX (50 μg/mL) for the indicated durations. (E) PTEN ubiquitination assays in CD8+ T cells stimulated with anti-CD3 and anti-CD28 antibodies in the presence of MG132. (F) Immunoblot analysis of the indicated proteins in CD8+ T cells from WT mice stimulated with anti-CD3 and anti-CD28 antibodies plus LMB for 2 hours. (G) PTEN SUMOylation assays using nuclear and cytoplasmic fractions of WT and KO CD8+ T cells stimulated with anti-CD3 and anti-CD28 antibodies for 2 hours. (H) Quantification of PTEN-SUMO2/3:PTEN levels in the cytoplasmic fractions of WT and KO CD8+ T cells stimulated with anti-CD3 and anti-CD28 antibodies for 2 hours (n = 4). (I) Immunoblot analysis of the indicated proteins in CD8+ T cells from WT mice stimulated with anti-CD3 and anti-CD28 antibodies plus LMB for 0, 2, and 4 hours. (J and K) PTEN SUMOylation (J) and ubiquitination (K) assays using nuclear and cytoplasmic fractions of CD8+ T cells from WT mice stimulated with anti-CD3 and anti-CD28 antibodies plus LMB for 2 hours. Data are representative of 3 independent experiments and presented as the mean ± SEM. *P < 0.05 and **P < 0.01, by Student’s t test.