2. Academic Validation
  3. SIRT2 negatively regulates the cGAS-STING pathway by deacetylating G3BP1

SIRT2 negatively regulates the cGAS-STING pathway by deacetylating G3BP1

  • EMBO Rep. 2023 Oct 23:e57500. doi: 10.15252/embr.202357500.
Yutong Li 1,  Juntao Bie 1,  Chen Song 1,  Yunfei Li 2,  Tianzhuo Zhang 1,  Haishuang Li 3,  Long Zhao 4,  Fuping You 2,  Jianyuan Luo 1 5
Affiliations

Affiliations

  • 1 Department of Medical Genetics, Center for Medical Genetics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
  • 2 Department of Immunology, School of Basic Medical Sciences, Beijing Key Laboratory of Tumor Systems Biology, Institute of Systems Biomedicine, Peking University Health Science Center, Beijing, China.
  • 3 Department of Pathology, School of Basic Medical Sciences, Peking University Third Hospital, Peking University Health Science Center, Beijing, China.
  • 4 Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China.
  • 5 Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
PMID: 37870259 DOI: 10.15252/embr.202357500
Abstract

SIRT2, a cytoplasmic member of the Sirtuin family, has important roles in immunity and inflammation. However, its function in regulating the response to DNA virus Infection remains elusive. Here, we find that SIRT2 is a unique regulator among the Sirtuin family that negatively modulates the cGAS-STING-signaling pathway. SIRT2 is down-regulated after Herpes simplex virus-1 (HSV-1) Infection, and SIRT2 deficiency markedly elevates the expression levels of type I interferon (IFN). SIRT2 inhibits the DNA binding ability and droplet formation of cGAS by interacting with and deacetylating G3BP1 at K257, K276, and K376, leading to the disassembly of the cGAS-G3BP1 complex, which is critical for cGAS activation. Administration of AGK2, a selective SIRT2 Inhibitor, protects mice from HSV-1 Infection and increases the expression of IFN and IFN-stimulated genes. Our study shows that SIRT2 negatively regulates cGAS activation through G3BP1 deacetylation, suggesting a potential Antiviral strategy by modulating SIRT2 activity.

Keywords

G3BP1; SIRT2; acetylation; cGAS; innate immunity.

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