He Xiadi, Wang Qiwei, Cheng Xin, Wang Weihua, Li Yutong, Nan Yabing, Wu Jiang, Xiu Bingqiu, Jiang Tao, Bergholz Johann S, Gu Hao, Chen Fuhui, Fan Guangjian, Sun Lianhui, Xie Shaozhen, Zou Junjie, Lin Sheng, Wei Yun, Lee James, Asara John M, Zhang Ke, Cantley Lewis C, Zhao Jean J
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, National Clinical Research Center for Metabolic Diseases (Shanghai), Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Lifecycle Health Management Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Cell. 2025 Apr 3;188(7):1858-1877.e21. doi: 10.1016/j.cell.2025.01.043. Epub 2025 Feb 28.
Vitamin C (vitC) is essential for health and shows promise in treating diseases like cancer, yet its mechanisms remain elusive. Here, we report that vitC directly modifies lysine residues to form "vitcyl-lysine"-a process termed vitcylation. Vitcylation occurs in a dose-, pH-, and sequence-dependent manner in both cell-free systems and living cells. Mechanistically, vitC vitcylates signal transducer and activator of transcription-1 (STAT1)- lysine-298 (K298), impairing its interaction with T cell protein-tyrosine phosphatase (TCPTP) and preventing STAT1-Y701 dephosphorylation. This leads to enhanced STAT1-mediated interferon (IFN) signaling in tumor cells, increased major histocompatibility complex (MHC)/human leukocyte antigen (HLA) class I expression, and activation of anti-tumor immunity in vitro and in vivo. The discovery of vitcylation as a distinctive post-translational modification provides significant insights into vitC's cellular function and therapeutic potential, opening avenues for understanding its biological effects and applications in disease treatment.
维生素C（vitC）对健康至关重要，在治疗癌症等疾病方面显示出前景，但其作用机制仍不清楚。在此，我们报告vitC直接修饰赖氨酸残基以形成“维生素C赖氨酸”——这一过程称为维生素C化。维生素C化在无细胞系统和活细胞中均以剂量、pH和序列依赖的方式发生。从机制上讲，vitC使信号转导和转录激活因子1（STAT1）的赖氨酸298（K298）发生维生素C化，损害其与T细胞蛋白酪氨酸磷酸酶（TCPTP）的相互作用，并阻止STAT1-Y701去磷酸化。这导致肿瘤细胞中STAT1介导的干扰素（IFN）信号增强，主要组织相容性复合体（MHC）/人类白细胞抗原（HLA）I类表达增加，并在体外和体内激活抗肿瘤免疫。维生素C化作为一种独特的翻译后修饰的发现，为vitC的细胞功能和治疗潜力提供了重要见解，为理解其生物学效应及其在疾病治疗中的应用开辟了道路。
