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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,10,22]]},"abstract":"<jats:p>\n                    RNA\n                    <jats:italic>N<\/jats:italic>\n                    <jats:sup>6<\/jats:sup>\n                    -methyladenosine (m\n                    <jats:sup>6<\/jats:sup>\n                    A) demethylase AlkB homolog 5 (ALKBH5) plays a crucial role in regulating innate immunity. Lysine acylation, a widespread protein modification, influences protein function, but its impact on ALKBH5 during viral infections has not been well characterized. This study investigates the presence and regulatory mechanisms of a previously unidentified lysine acylation in ALKBH5 and its role in mediating m\n                    <jats:sup>6<\/jats:sup>\n                    A modifications to activate antiviral innate immune responses. We demonstrate that ALKBH5 undergoes lactylation, which is essential for an effective innate immune response against DNA herpesviruses, including herpes simplex virus type 1 (HSV-1), Kaposi\u2019s sarcoma\u2013associated herpesvirus (KSHV), and mpox virus (MPXV). This lactylation attenuates viral replication. Mechanistically, viral infections enhance ALKBH5 lactylation by increasing its interaction with acetyltransferase ESCO2 and decreasing its interaction with deacetyltransferase SIRT6. Lactylated ALKBH5 binds interferon-beta (IFN-\u03b2) messenger RNA (mRNA), leading to demethylation of its m\n                    <jats:sup>6<\/jats:sup>\n                    A modifications and promoting IFN-\u03b2 mRNA biogenesis. Overexpression of ESCO2 or depletion of SIRT6 further enhances ALKBH5 lactylation to strengthen IFN-\u03b2 mRNA biogenesis. Our results identify a posttranslational modification of ALKBH5 and its role in regulating antiviral innate immune responses through m\n                    <jats:sup>6<\/jats:sup>\n                    A modification. The finding provides an understanding of innate immunity and offers a potential therapeutic target for HSV-1, KSHV, and MPXV infections.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2409132121","type":"journal-article","created":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T13:33:19Z","timestamp":1729085599000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":47,"title":["Lactylation of RNA m\n                    <sup>6<\/sup>\n                    A demethylase ALKBH5 promotes innate immune response to DNA herpesviruses and mpox virus"],"prefix":"10.1073","volume":"121","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5675-2429","authenticated-orcid":false,"given":"Wan","family":"Li","sequence":"first","affiliation":[{"name":"Department of Gynecology, Women\u2019s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing 210004, People\u2019s Republic of China"},{"name":"Department of Microbiology, Nanjing Medical University, Nanjing 211166, People\u2019s Republic of China"},{"name":"Changzhou Medical Center, Nanjing Medical University, Nanjing 211166, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Nanjing Medical University, Nanjing 211166, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Nanjing Medical University, Nanjing 211166, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Nanjing Medical University, Nanjing 211166, People\u2019s Republic of 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China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangchen","family":"Zhao","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Medical Key Laboratory of Pathogenic Microbiology in Emerging Major Infectious Diseases, National Health Commission (NHC) Key Laboratory of Enteric Pathogenic Microbiology, Jiangsu Provincial Center for Disease Control and Prevention, Nanjing 210009, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3974-0298","authenticated-orcid":false,"given":"Qin","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Nanjing Medical University, Nanjing 211166, People\u2019s Republic of China"},{"name":"Changzhou Medical Center, Nanjing Medical University, Nanjing 211166, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zongzheng","family":"Zhao","sequence":"additional","affiliation":[{"name":"Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun 130122, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Li","sequence":"additional","affiliation":[{"name":"Changchun Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Changchun 130122, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guochun","family":"Chen","sequence":"additional","affiliation":[{"name":"Changzhou Medical Center, Nanjing Medical University, Nanjing 211166, People\u2019s Republic of China"},{"name":"Department of Infectious Diseases, Changzhou Third People\u2019s Hospital, Changzhou 213000, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Jia","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Women\u2019s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing Medical University, Nanjing 210004, People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shou-Jiang","family":"Gao","sequence":"additional","affiliation":[{"name":"Tumor Virology Program, University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA 15232"},{"name":"Department of Microbiology and Molecular Genetics, University of Pittsburgh, Pittsburgh, PA 15232"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Gynecology, Women\u2019s Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, 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Li Lactylation of RNA m6A demethylase ALKBH5 promotes innate immune response to DNA herpesviruses and monkeypox virus. Baidu Netdisk. https:\/\/pan.baidu.com\/s\/1enuYf9AlfsJYLGH09H2o9A?pwd=gc7y. Deposited 1 October 2024."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2409132121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,16]],"date-time":"2024-10-16T13:33:26Z","timestamp":1729085606000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2409132121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,16]]},"references-count":61,"journal-issue":{"issue":"43","published-print":{"date-parts":[[2024,10,22]]}},"alternative-id":["10.1073\/pnas.2409132121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2409132121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,16]]},"assertion":[{"value":"2024-05-08","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-31","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-10-16","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2409132121"}}