Journal article
SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19
Cell reports (Cambridge), Vol.44(4), 115562
04/11/2025
DOI: 10.1016/j.celrep.2025.115562
PMCID: PMC12074670
PMID: 40220296
Abstract
Aging-associated vulnerability to coronavirus disease 2019 (COVID-19) remains poorly understood. Here, we show that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected aged mice lacking SIRT2, a cytosolic NAD+-dependent deacetylase, develop more severe disease and show increased mortality, while treatment with an NAD+ booster, 78c, protects aged mice from lethal infection. Mechanistically, we demonstrate that SIRT2 modulates the acetylation of cyclic GMP-AMP synthase (cGAS), an immune sensor for cytosolic DNA, and suppresses aging-associated cGAS activation and inflammation. Furthermore, we show that SARS-CoV-2 infection-induced inflammation is mediated at least in part by ORF3a, which triggers mtDNA release and cGAS activation. Collectively, our study reveals a molecular basis for aging-associated susceptibility to COVID-19 and suggests therapeutic approaches to protect aged populations from severe SARS-CoV-2 infection.
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•SIRT2 and NAD+ boosting protect against aging-associated severe COVID-19•SARS-CoV-2 ORF3a induces mitochondrial DNA release, cGAS activation, and inflammation•SIRT2 deacetylates cGAS and inhibits aging-associated cGAS activation and inflammation
Barthez et al. show that SIRT2 and NAD+ boosting protect against aging-associated severe COVID-19. SARS-CoV-2-induced inflammation is mediated by ORF3a, which triggers mtDNA release and cGAS activation. SIRT2 deacetylates cGAS and suppresses aging-associated cGAS activation and inflammation. This study has implications for protecting aged populations from severe SARS-CoV-2 infection.
Details
- Title: Subtitle
- SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19
- Creators
- Marine Barthez - University of California, BerkeleyBiyun Xue - University of IowaJian Zheng - University of LouisvilleYifei Wang - University of California, BerkeleyZehan Song - University of California, BerkeleyWei-Chieh Mu - University of California, BerkeleyChih-ling Wang - University of California, BerkeleyJiayue Guo - University of California, BerkeleyFanghan Yang - University of California, BerkeleyYuze Ma - University of California, BerkeleyXuetong Wei - University of California, BerkeleyChengjin Ye - Texas Biomedical Research InstituteNicholas Sims - University of California, BerkeleyLuis Martinez-Sobrido - Texas Biomedical Research InstituteStanley Perlman - Department of Microbiology and Immunology, University of Iowa, Iowa City, IA, USADanica Chen - University of California, Berkeley
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.44(4), 115562
- DOI
- 10.1016/j.celrep.2025.115562
- PMID
- 40220296
- PMCID
- PMC12074670
- NLM abbreviation
- Cell Rep
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Publisher
- Elsevier Inc
- Grant note
- NIH: R01DK 117481, R01AG063404, R01AG 063389, R01AG082105, P01AI060699, R01 AI129269 National Institute of Food and AgricultureAFAR FellowshipDr. and Mrs. James C.Y. Soong FellowshipTaiwan Government for Study Abroad ScholarshipQB3 Frontiers in Medical Research FellowshipCIRM Fellowship
We thank S. Ruzin, D. Schichnes, and the Berkeley Imaging Facility for imaging experiments; J. Hurley and X. Ren for the ORF3a, E, and ORF8 constructs; and R. Vance for the cGAS construct. This work was supported by NIH R01DK 117481 (to D.C.) , R01AG063404 (to D.C.) , R01AG 063389 (to D.C.) , R01AG082105 (to D.C.) , P01AI060699 (to S.P.) , and R01 AI129269 (to S.P.) ; the National Institute of Food and Agriculture (to D.C.) , an AFAR Fellowship (to Y.W.) ; the Dr. and Mrs. James C.Y. Soong Fellowship (to W.-C.M.) ; the Taiwan Government for Study Abroad Scholarship (to W.-C.M.) ; the QB3 Frontiers in Medical Research Fellowship (to W.-C.M.) ; and the CIRM Fellowship (to J.G.) .
- Language
- English
- Date published
- 04/11/2025
- Academic Unit
- Microbiology and Immunology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Infectious Disease (Pediatrics); Internal Medicine
- Record Identifier
- 9984811214402771
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