2. Academic Validation
  3. UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumor immunity

UFL1 ablation in T cells suppresses PD-1 UFMylation to enhance anti-tumor immunity

  • Mol Cell. 2024 Feb 9:S1097-2765(24)00091-1. doi: 10.1016/j.molcel.2024.01.024.
Chuan He 1,  Xixin Xing 1,  Hsin-Yi Chen 2,  Minling Gao 1,  Jie Shi 1,  Bolin Xiang 1,  Xiangling Xiao 1,  Yishuang Sun 1,  Haisheng Yu 1,  Gaoshan Xu 1,  Yingmeng Yao 1,  Zuosong Xie 1,  Yujie Xing 3,  Bugi Ratno Budiarto 4,  Shih-Yu Chen 2,  Yang Gao 3,  Yu-Ru Lee 5,  Jinfang Zhang 6
Affiliations

Affiliations

  • 1 Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China.
  • 2 Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan.
  • 3 Department of Urology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
  • 4 Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan; Taiwan International Graduate Program in Molecular Medicine, National Yang Ming Chiao Tung University and Academia Sinica, Taipei, Taiwan.
  • 5 Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan. Electronic address: yrlee@ibms.sinica.edu.tw.
  • 6 Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China; Taikang Center for Life and Medical Sciences, Wuhan University, Wuhan 430071, China. Electronic address: jinfang_zhang@whu.edu.cn.
PMID: 38377992 DOI: 10.1016/j.molcel.2024.01.024
Abstract

UFMylation is an emerging ubiquitin-like post-translational modification that regulates various biological processes. Dysregulation of the UFMylation pathway leads to human diseases, including cancers. However, the physiological role of UFMylation in T cells remains unclear. Here, we report that mice with conditional knockout (cKO) Ufl1, a UFMylation E3 ligase, in T cells exhibit effective tumor control. Single-cell RNA sequencing analysis shows that tumor-infiltrating cytotoxic CD8+ T cells are increased in Ufl1 cKO mice. Mechanistically, UFL1 promotes PD-1 UFMylation to antagonize PD-1 ubiquitination and degradation. Furthermore, AMPK phosphorylates UFL1 at Thr536, disrupting PD-1 UFMylation to trigger its degradation. Of note, UFL1 ablation in T cells reduces PD-1 UFMylation, subsequently destabilizing PD-1 and enhancing CD8+ T cell activation. Thus, Ufl1 cKO mice bearing tumors have a better response to anti-CTLA-4 immunotherapy. Collectively, our findings uncover a crucial role of UFMylation in T cells and highlight UFL1 as a potential target for Cancer treatment.

Keywords

AMPK; PD-1; UFL1; UFMylation; tumor immunotherapy.

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