Deactylation by SIRT1 enables liquid-liquid phase separation of IRF3/IRF7 in innate antiviral immunity.

Ziran Qin, Xiuwu Fang, Wenhuan Sun, Zhenyu Ma, Tong Dai, Shuai Wang, Zhi Zong, Huizhe Huang, Heng Ru, Huasong Lu, Bing Yang, Shixian Lin, Fangfang Zhou, Long Zhang

Nature immunology 2022 Aug

filter terms:

Innate antiviral immunity deteriorates with aging but how this occurs is not entirely clear. Here we identified SIRT1-mediated DNA-binding domain (DBD) deacetylation as a critical step for IRF3/7 activation that is inhibited during aging. Viral-stimulated IRF3 underwent liquid-liquid phase separation (LLPS) with interferon (IFN)-stimulated response element DNA and compartmentalized IRF7 in the nucleus, thereby stimulating type I IFN (IFN-I) expression. SIRT1 deficiency resulted in IRF3/IRF7 hyperacetylation in the DBD, which inhibited LLPS and innate immunity, resulting in increased viral load and mortality in mice. By developing a genetic code expansion orthogonal system, we demonstrated the presence of an acetyl moiety at specific IRF3/IRF7 DBD site/s abolish IRF3/IRF7 LLPS and IFN-I induction. SIRT1 agonists rescued SIRT1 activity in aged mice, restored IFN signaling and thus antagonized viral replication. These findings not only identify a mechanism by which SIRT1 regulates IFN production by affecting IRF3/IRF7 LLPS, but also provide information on the drivers of innate immunosenescence. © 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.

Citation

Ziran Qin, Xiuwu Fang, Wenhuan Sun, Zhenyu Ma, Tong Dai, Shuai Wang, Zhi Zong, Huizhe Huang, Heng Ru, Huasong Lu, Bing Yang, Shixian Lin, Fangfang Zhou, Long Zhang. Deactylation by SIRT1 enables liquid-liquid phase separation of IRF3/IRF7 in innate antiviral immunity. Nature immunology. 2022 Aug;23(8):1193-1207