SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19
Summary: 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 inc...
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| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2025-04-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112472500333X |
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| author | Marine Barthez Biyun Xue Jian Zheng Yifei Wang Zehan Song Wei-Chieh Mu Chih-ling Wang Jiayue Guo Fanghan Yang Yuze Ma Xuetong Wei Chengjin Ye Nicholas Sims Luis Martinez-Sobrido Stanley Perlman Danica Chen |
| author_facet | Marine Barthez Biyun Xue Jian Zheng Yifei Wang Zehan Song Wei-Chieh Mu Chih-ling Wang Jiayue Guo Fanghan Yang Yuze Ma Xuetong Wei Chengjin Ye Nicholas Sims Luis Martinez-Sobrido Stanley Perlman Danica Chen |
| author_sort | Marine Barthez |
| collection | DOAJ |
| description | Summary: 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. |
| format | Article |
| id | doaj-art-dbc2cbe04a1841bbbc57ce6f981abec3 |
| institution | DOAJ |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-dbc2cbe04a1841bbbc57ce6f981abec32025-08-20T03:03:36ZengElsevierCell Reports2211-12472025-04-0144411556210.1016/j.celrep.2025.115562SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19Marine Barthez0Biyun Xue1Jian Zheng2Yifei Wang3Zehan Song4Wei-Chieh Mu5Chih-ling Wang6Jiayue Guo7Fanghan Yang8Yuze Ma9Xuetong Wei10Chengjin Ye11Nicholas Sims12Luis Martinez-Sobrido13Stanley Perlman14Danica Chen15Department of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USADepartment of Microbiology and Immunology, University of Iowa, Iowa City, IA, USADepartment of Microbiology and Immunology, Center for Predictive Medicine, University of Louisville, Louisville, KY, USADepartment of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USADepartment of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USADepartment of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USADepartment of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USADepartment of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USADepartment of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USADepartment of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USADepartment of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USATexas Biomedical Research Institute, San Antonio, TX, USADepartment of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USATexas Biomedical Research Institute, San Antonio, TX, USADepartment of Microbiology and Immunology, University of Iowa, Iowa City, IA, USA; Department of Pediatrics, University of Iowa, Iowa City, IA, USA; Corresponding authorDepartment of Nutritional Sciences and Toxicology, University of California, Berkeley, Berkeley, CA 94720, USA; Metabolic Biology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Endocrinology Graduate Program, University of California, Berkeley, Berkeley, CA 94720, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S221112472500333XCP: ImmunologyCP: Microbiology |
| spellingShingle | Marine Barthez Biyun Xue Jian Zheng Yifei Wang Zehan Song Wei-Chieh Mu Chih-ling Wang Jiayue Guo Fanghan Yang Yuze Ma Xuetong Wei Chengjin Ye Nicholas Sims Luis Martinez-Sobrido Stanley Perlman Danica Chen SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19 Cell Reports CP: Immunology CP: Microbiology |
| title | SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19 |
| title_full | SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19 |
| title_fullStr | SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19 |
| title_full_unstemmed | SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19 |
| title_short | SIRT2 suppresses aging-associated cGAS activation and protects aged mice from severe COVID-19 |
| title_sort | sirt2 suppresses aging associated cgas activation and protects aged mice from severe covid 19 |
| topic | CP: Immunology CP: Microbiology |
| url | http://www.sciencedirect.com/science/article/pii/S221112472500333X |
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