KAT5 acetylates cGAS to promote innate immune response to DNA virus
The DNA sensor cGMP-AMP synthase (cGAS) senses cytosolic microbial or self DNA to initiate a MITA/STING-dependent innate immune response. cGAS is regulated by various posttranslational modifications at its C-terminal catalytic domain. Whether and how its N-terminal unstructured domain is regulated b...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2020-09, Vol.117 (35), p.21568-21575 |
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| container_title | Proceedings of the National Academy of Sciences - PNAS |
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| creator | Song, Ze-Min Lin, Heng Yi, Xue-Mei Guo, Wei Hu, Ming-Ming Shu, Hong-Bing |
| description | The DNA sensor cGMP-AMP synthase (cGAS) senses cytosolic microbial or self DNA to initiate a MITA/STING-dependent innate immune response. cGAS is regulated by various posttranslational modifications at its C-terminal catalytic domain. Whether and how its N-terminal unstructured domain is regulated by posttranslational modifications remain unknown. We identified the acetyltransferase KAT5 as a positive regulator of cGAS-mediated innate immune signaling. Overexpression of KAT5 potentiated viral-DNA–triggered transcription of downstream antiviral genes, whereas a KAT5 deficiency had the opposite effects. Mice with inactivated Kat5 exhibited lower levels of serum cytokines in response to DNA virus infection, higher viral titers in the brains, and more susceptibility to DNA-virus–induced death. Mechanistically, KAT5 catalyzed acetylation of cGAS at multiple lysine residues in its N-terminal domain, which promoted its DNA-binding ability. Our findings suggest that KAT5-mediated cGAS acetylation at its N terminus is important for efficient innate immune response to DNA virus. |
| doi_str_mv | 10.1073/pnas.1922330117 |
| format | Article |
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Whether and how its N-terminal unstructured domain is regulated by posttranslational modifications remain unknown. We identified the acetyltransferase KAT5 as a positive regulator of cGAS-mediated innate immune signaling. Overexpression of KAT5 potentiated viral-DNA–triggered transcription of downstream antiviral genes, whereas a KAT5 deficiency had the opposite effects. Mice with inactivated Kat5 exhibited lower levels of serum cytokines in response to DNA virus infection, higher viral titers in the brains, and more susceptibility to DNA-virus–induced death. Mechanistically, KAT5 catalyzed acetylation of cGAS at multiple lysine residues in its N-terminal domain, which promoted its DNA-binding ability. Our findings suggest that KAT5-mediated cGAS acetylation at its N terminus is important for efficient innate immune response to DNA virus.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1922330117</identifier><identifier>PMID: 32817552</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Acetylation ; Acetyltransferase ; Animals ; Biological Sciences ; Cyclic GMP ; Cyclic GMP - metabolism ; Cytokines ; Deoxyribonucleic acid ; DNA ; DNA Virus Infections - genetics ; DNA Virus Infections - immunology ; DNA Virus Infections - metabolism ; DNA Viruses - genetics ; DNA Viruses - immunology ; Domains ; Female ; HEK293 Cells ; HeLa Cells ; Host-Pathogen Interactions ; Humans ; Immune response ; Immune system ; Immunity, Innate ; Innate immunity ; Interferon-beta - immunology ; Lysine ; Lysine Acetyltransferase 5 - genetics ; Lysine Acetyltransferase 5 - immunology ; Lysine Acetyltransferase 5 - metabolism ; Male ; Mice ; Mice, Knockout ; Microorganisms ; Nitric Oxide Synthase - genetics ; Nitric Oxide Synthase - metabolism ; Nucleotidyltransferases - genetics ; Nucleotidyltransferases - immunology ; Nucleotidyltransferases - metabolism ; Protein Processing, Post-Translational ; Signal Transduction ; Transcription ; Viral Proteins - metabolism ; Viruses</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2020-09, Vol.117 (35), p.21568-21575</ispartof><rights>Copyright National Academy of Sciences Sep 1, 2020</rights><rights>2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c410t-86b8b63a7166452c766ba1175ccaf9bcbc2581f467351f271659427b5f2e2ea03</citedby><cites>FETCH-LOGICAL-c410t-86b8b63a7166452c766ba1175ccaf9bcbc2581f467351f271659427b5f2e2ea03</cites><orcidid>0000-0001-9102-3272</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/26968831$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/26968831$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,314,727,780,784,803,885,27915,27916,53782,53784,58008,58241</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32817552$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Song, Ze-Min</creatorcontrib><creatorcontrib>Lin, Heng</creatorcontrib><creatorcontrib>Yi, Xue-Mei</creatorcontrib><creatorcontrib>Guo, Wei</creatorcontrib><creatorcontrib>Hu, Ming-Ming</creatorcontrib><creatorcontrib>Shu, Hong-Bing</creatorcontrib><title>KAT5 acetylates cGAS to promote innate immune response to DNA virus</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The DNA sensor cGMP-AMP synthase (cGAS) senses cytosolic microbial or self DNA to initiate a MITA/STING-dependent innate immune response. cGAS is regulated by various posttranslational modifications at its C-terminal catalytic domain. Whether and how its N-terminal unstructured domain is regulated by posttranslational modifications remain unknown. We identified the acetyltransferase KAT5 as a positive regulator of cGAS-mediated innate immune signaling. Overexpression of KAT5 potentiated viral-DNA–triggered transcription of downstream antiviral genes, whereas a KAT5 deficiency had the opposite effects. Mice with inactivated Kat5 exhibited lower levels of serum cytokines in response to DNA virus infection, higher viral titers in the brains, and more susceptibility to DNA-virus–induced death. Mechanistically, KAT5 catalyzed acetylation of cGAS at multiple lysine residues in its N-terminal domain, which promoted its DNA-binding ability. Our findings suggest that KAT5-mediated cGAS acetylation at its N terminus is important for efficient innate immune response to DNA virus.</description><subject>Acetylation</subject><subject>Acetyltransferase</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>Cyclic GMP</subject><subject>Cyclic GMP - metabolism</subject><subject>Cytokines</subject><subject>Deoxyribonucleic acid</subject><subject>DNA</subject><subject>DNA Virus Infections - genetics</subject><subject>DNA Virus Infections - immunology</subject><subject>DNA Virus Infections - metabolism</subject><subject>DNA Viruses - genetics</subject><subject>DNA Viruses - immunology</subject><subject>Domains</subject><subject>Female</subject><subject>HEK293 Cells</subject><subject>HeLa Cells</subject><subject>Host-Pathogen Interactions</subject><subject>Humans</subject><subject>Immune response</subject><subject>Immune system</subject><subject>Immunity, Innate</subject><subject>Innate immunity</subject><subject>Interferon-beta - immunology</subject><subject>Lysine</subject><subject>Lysine Acetyltransferase 5 - genetics</subject><subject>Lysine Acetyltransferase 5 - immunology</subject><subject>Lysine Acetyltransferase 5 - metabolism</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Knockout</subject><subject>Microorganisms</subject><subject>Nitric Oxide Synthase - genetics</subject><subject>Nitric Oxide Synthase - metabolism</subject><subject>Nucleotidyltransferases - genetics</subject><subject>Nucleotidyltransferases - immunology</subject><subject>Nucleotidyltransferases - metabolism</subject><subject>Protein Processing, Post-Translational</subject><subject>Signal Transduction</subject><subject>Transcription</subject><subject>Viral Proteins - metabolism</subject><subject>Viruses</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkD1PwzAYhC0EoqUwM4EiMaf42_GCVBUoiAoGymw5xoFUTRxsp1L_PYlaCkw33PPeezoAzhEcIyjIdVPrMEYSY0IgQuIADBGUKOVUwkMwhBCLNKOYDsBJCEsIoWQZPAYDgjMkGMNDMH2aLFiijY2blY42JGY2eU2iSxrvKhdtUta17qWq2tom3obG1cH2xO3zJFmXvg2n4KjQq2DPdjoCb_d3i-lDOn-ZPU4n89RQBGOa8TzLOdECcU4ZNoLzXHelmTG6kLnJDWYZKigXhKECdxiTFIucFdhiqyEZgZttbtPmlX03to5er1Tjy0r7jXK6VP-duvxUH26tBBWUQ9kFXO0CvPtqbYhq6Vpfd50VprR7LAnuqestZbwLwdti_wFB1a-u-tXV7-rdxeXfYnv-Z-YOuNgCyxCd3_uYS55lBJFvWNCGsw</recordid><startdate>20200901</startdate><enddate>20200901</enddate><creator>Song, Ze-Min</creator><creator>Lin, Heng</creator><creator>Yi, Xue-Mei</creator><creator>Guo, Wei</creator><creator>Hu, Ming-Ming</creator><creator>Shu, Hong-Bing</creator><general>National Academy of Sciences</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0001-9102-3272</orcidid></search><sort><creationdate>20200901</creationdate><title>KAT5 acetylates cGAS to promote innate immune response to DNA virus</title><author>Song, Ze-Min ; 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Whether and how its N-terminal unstructured domain is regulated by posttranslational modifications remain unknown. We identified the acetyltransferase KAT5 as a positive regulator of cGAS-mediated innate immune signaling. Overexpression of KAT5 potentiated viral-DNA–triggered transcription of downstream antiviral genes, whereas a KAT5 deficiency had the opposite effects. Mice with inactivated Kat5 exhibited lower levels of serum cytokines in response to DNA virus infection, higher viral titers in the brains, and more susceptibility to DNA-virus–induced death. Mechanistically, KAT5 catalyzed acetylation of cGAS at multiple lysine residues in its N-terminal domain, which promoted its DNA-binding ability. Our findings suggest that KAT5-mediated cGAS acetylation at its N terminus is important for efficient innate immune response to DNA virus.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>32817552</pmid><doi>10.1073/pnas.1922330117</doi><tpages>8</tpages><orcidid>https://orcid.org/0000-0001-9102-3272</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Acetylation Acetyltransferase Animals Biological Sciences Cyclic GMP Cyclic GMP - metabolism Cytokines Deoxyribonucleic acid DNA DNA Virus Infections - genetics DNA Virus Infections - immunology DNA Virus Infections - metabolism DNA Viruses - genetics DNA Viruses - immunology Domains Female HEK293 Cells HeLa Cells Host-Pathogen Interactions Humans Immune response Immune system Immunity, Innate Innate immunity Interferon-beta - immunology Lysine Lysine Acetyltransferase 5 - genetics Lysine Acetyltransferase 5 - immunology Lysine Acetyltransferase 5 - metabolism Male Mice Mice, Knockout Microorganisms Nitric Oxide Synthase - genetics Nitric Oxide Synthase - metabolism Nucleotidyltransferases - genetics Nucleotidyltransferases - immunology Nucleotidyltransferases - metabolism Protein Processing, Post-Translational Signal Transduction Transcription Viral Proteins - metabolism Viruses |
| title | KAT5 acetylates cGAS to promote innate immune response to DNA virus |
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