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

  • Nat Immunol. 2022 Aug;23(8):1193-1207. doi: 10.1038/s41590-022-01269-0.
Ziran Qin   #  1  2 ,  Xiuwu Fang   #  2 ,  Wenhuan Sun  2 ,  Zhenyu Ma  2 ,  Tong Dai  2 ,  Shuai Wang  2 ,  Zhi Zong  3 ,  Huizhe Huang  4 ,  Heng Ru  3 ,  Huasong Lu  3 ,  Bing Yang  3  5 ,  Shixian Lin  3 ,  Fangfang Zhou  6 ,  Long Zhang  7  8  9
Affiliations
  • 1. International Biomed-X Research Center, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
  • 2. Institutes of Biology and Medical Science, Soochow University, Suzhou, China.
  • 3. MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 4. Faculty of Basic Medical Sciences, Chonqing Medical University, Chongqing, China.
  • 5. Department of Pharmaceutical Chemistry and the Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
  • 6. Institutes of Biology and Medical Science, Soochow University, Suzhou, China. [email protected].
  • 7. International Biomed-X Research Center, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China. [email protected].
  • 8. MOE Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, China. [email protected].
  • 9. Cancer Center, Zhejiang University, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 35879450 DOI: 10.1038/s41590-022-01269-0
Abstract

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.

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