Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response by Xiadi He, Qiwei Wang, Xin Cheng, ..., instant download

Lysine vitcylation is a vitamin C-derived protein modification that enhances STAT1-mediated immune response by Xiadi He, Qiwei Wang, Xin Cheng, ..., instant download

SUMMARYVitamin C (vitC) is essential for health and shows promise in treating diseases like cancer, yet its mechanismsremain elusive. Here, we report that vitC directly modifies lysine residues to form ‘‘vitcyl-lysine’’—a processtermed 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) andpreventing 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 vitcylationas a distinctive post-translational modification provides significant insights into vitC’s cellular function andtherapeutic potential, opening avenues for understanding its biological effects and applications in diseasetreatment.