Pyruvate is a natural suppressor of interferon signaling by inducing STAT1 protein pyruvylation, 2026, Zuo et al.

[SNT Gatchaman]

Pyruvate is a natural suppressor of interferon signaling by inducing STAT1 protein pyruvylation

Spoiler: Authors

Yibo Zuo; Qin Wang; Wanying Tian; Xinhe Wang; Zhijin Zheng; Wei He; Renxia Zhang; Qian Zhao; Ying Miao; Yukang Yuan; Tingting Zhang; Qun 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.

HIGHLIGHTS
• Pyruvate is a natural suppressor of IFN-I immune activity

• PKM2 and pyruvate promote STAT1 pyruvylation at Lys201

• STAT1 pyruvylation inhibits STAT1-STAT2 binding and IFN-I signaling

• Inhibition of STAT1 pyruvylation enhances in vivo antiviral immunity

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[SNT Gatchaman]

The glycolysis pathway has long been recognized as a source of diverse intermediate metabolites for other metabolic pathways. […] Notably, glycolysis is intimately associated with specific immune responses. It has been reported that the glycolytic metabolite lactate can induce histone lactylation modification, thereby regulating gene expression.

Here, this study identifies protein pyruvylation mediated by pyruvate, the terminal product of glycolysis. The role of pyruvate as a small-molecule modifier of proteins expands its functional repertoire beyond canonical metabolic pathways. Thus, this study promotes understanding the significance of both glycolysis and pyruvate-mediated protein PTM.

In this study, we found that STAT1, a central component of the IFN-I signaling pathway, is covalently modified by pyruvate to form protein pyruvylation. We further demonstrated that high glucose promotes STAT1 protein pyruvylation at Lys201, which in turn blocks STAT1-STAT2 interaction induced by IFN-I, eventually inhibiting the strength of IFN-I signaling. Given the critical role of IFN-I in antiviral immunity, STAT1 protein pyruvylation provides a mechanistic link between pyruvate and impaired antiviral immunity during viral infections.