Yibo Zuo, Qin Wang, Wanying Tian, Xinhe Wang, Zhijin Zheng, Wei He, Renxia Zhang, Qian Zhao, Ying Miao, Yukang Yuan, Tingting Zhang, Qi Cui, Yuerong Zhang, Chunyan Liu, Haiyan Zhou, Hui Zheng
Glycolysis is a central metabolic pathway that converts glucose into pyruvate. Although pyruvate has been well documented to be a key and terminal metabolite of glycolysis with both energetic and biosynthetic roles, its non-metabolic functions remain unexplored. Here, we report a pyruvate-mediated protein post-translational modification (PTM), protein pyruvylation. We reveal that high glucose-upregulated glycolysis promotes signal transducer and activator of transcription 1 (STAT1) pyruvylation at Lys201 (K201), which blocks STAT1 and signal transducer and activator of transcription 2 (STAT2) interaction, thus suppressing type I interferon (IFN-I) signaling and antiviral immune activity. Consequently, STAT1-K201R knockin mice exhibit enhanced IFN-I antiviral immunity. Importantly, high glucose promotes STAT1 pyruvylation and attenuates immune response to either virus infection or IFN-I treatment in humans. This study identifies the protein pyruvylation modification, reveals a non-metabolic function of the metabolite pyruvate, and provides insights into how high glucose impairs IFN-I antiviral immunity through pyruvate, offering strategies to improve IFN-I immune activity for both preventing and treating viral infections.