He Chuan, Xing Xixin, Chen Hsin-Yi, Gao Minling, Shi Jie, Xiang Bolin, Xiao Xiangling, Sun Yishuang, Yu Haisheng, Xu Gaoshan, Yao Yingmeng, Xie Zuosong, Xing Yujie, Budiarto Bugi Ratno, Chen Shih-Yu, Gao Yang, Lee Yu-Ru, Zhang Jinfang
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.
Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan.
Mol Cell. 2024 Mar 21;84(6):1120-1138.e8. doi: 10.1016/j.molcel.2024.01.024. Epub 2024 Feb 19.
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.
UFMylation是一种新兴的类泛素化翻译后修饰，可调节多种生物学过程。UFMylation途径的失调会导致包括癌症在内的人类疾病。然而，UFMylation在T细胞中的生理作用仍不清楚。在这里，我们报告说，在T细胞中条件性敲除（cKO）Ufl1（一种UFMylation E3连接酶）的小鼠表现出有效的肿瘤控制。单细胞RNA测序分析表明，Ufl1 cKO小鼠中肿瘤浸润性细胞毒性CD8 T细胞增加。从机制上讲，UFL1促进PD-1的UFMylation，以拮抗PD-1的泛素化和降解。此外，AMPK在Thr536处磷酸化UFL1，破坏PD-1的UFMylation以触发其降解。值得注意的是，T细胞中UFL1的缺失会降低PD-1的UFMylation，随后使PD-1不稳定并增强CD8 T细胞的活化。因此，携带肿瘤的Ufl1 cKO小鼠对抗CTLA-4免疫疗法有更好的反应。总的来说，我们的发现揭示了UFMylation在T细胞中的关键作用，并突出了UFL1作为癌症治疗的潜在靶点。
