{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T04:31:36Z","timestamp":1788237096243,"version":"build-2803163510"},"update-to":[{"DOI":"10.1371\/journal.ppat.1013755","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000}}],"reference-count":51,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["23fk0108595j0101"],"award-info":[{"award-number":["23fk0108595j0101"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["23fk0108595j0001"],"award-info":[{"award-number":["23fk0108595j0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development","doi-asserted-by":"publisher","award":["243fa827012j0302"],"award-info":[{"award-number":["243fa827012j0302"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["22K08616"],"award-info":[{"award-number":["22K08616"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["23K27641"],"award-info":[{"award-number":["23K27641"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>N6-methyladenosine (m6A) epitranscriptomic modifications play crucial roles in regulating both host and viral gene expression. Here, we revealed a novel mechanism by which paramyxoviruses exploit host m6A machinery to simultaneously enhance viral replication and suppress host immunity. Our results demonstrated that the viral matrix protein (M) of bovine parainfluenza virus type 3 (BPIV3) binds to the methyltransferase domain of METTL3 in the nucleus and facilitates its translocation to the cytoplasm through an exportin-1-dependent pathway. This mechanism is conserved across multiple paramyxoviruses, including human parainfluenza virus type 3, Sendai virus, Nipah virus, and measles virus, suggesting an evolutionarily conserved viral strategy. The relocated METTL3 catalyzes m6A modification at specific sites within viral nucleocapsid protein (N) mRNA, significantly enhancing its stability and protein expression. Using reverse genetics, we generated recombinant viruses harbouring mutations at these m6A acceptor sites, which exhibited markedly attenuated viral replication, confirming the critical role of these epitranscriptomic marks in the viral life cycle. Rescue experiments demonstrated that the expression of exogenous N protein partially restored the viral titer and concomitant genome\/antigenome synthesis in m6A site mutant, indicating that reduced N protein abundance represents a key mechanism underlying impaired viral replication. Furthermore, M protein-mediated depletion of nuclear METTL3 significantly reduces m6A modification of host IFN-\u03b2 mRNA, resulting in diminished interferon expression and compromised antiviral responses. Supporting this mechanism, infection with viruses bearing nuclear export signal mutations that prevent METTL3 cytoplasmic translocation, maintained IFN-\u03b2 mRNA m6A modification and resulted in significantly elevated IFN-\u03b2 expression. These findings provide direct mechanistic evidence that paramyxoviruses utilize M-driven METTL3 relocalization as a sophisticated immune evasion strategy. Our study illuminates how paramyxoviruses strategically manipulate epitranscriptomic regulation to create an environment conducive to viral propagation, thereby advancing our understanding of virus-host interactions and identifying potential targets for antiviral therapeutics.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013755","type":"journal-article","created":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T18:44:41Z","timestamp":1764614681000},"page":"e1013755","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Paramyxovirus matrix protein redirects METTL3 for dual regulation of viral replication and immune evasion"],"prefix":"10.1371","volume":"21","author":[{"given":"Takashi","family":"Okura","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Nakai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taichi","family":"Kameya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fuminori","family":"Mizukoshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiyori","family":"Okura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatoshi","family":"Kakizaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumihiro","family":"Kato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yusuke","family":"Matsumoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichiro","family":"Nakatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoru","family":"Takeuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirokazu","family":"Kimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makoto","family":"Takeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noriyuki","family":"Otsuki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuya","family":"Shirato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideki","family":"Hasegawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6019-958X","authenticated-orcid":true,"given":"Akihide","family":"Ryo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,12,1]]},"reference":[{"issue":"10","key":"ppat.1013755.ref001","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1038\/s41579-020-0382-3","article-title":"Epigenetic and epitranscriptomic regulation of viral replication","volume":"18","author":"K Tsai","year":"2020","journal-title":"Nat Rev Microbiol"},{"issue":"8","key":"ppat.1013755.ref002","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.3390\/v14081666","article-title":"The Impact of Epitranscriptomics on Antiviral Innate Immunity","volume":"14","author":"B Mersinoglu","year":"2022","journal-title":"Viruses"},{"key":"ppat.1013755.ref003","doi-asserted-by":"crossref","first-page":"1245683","DOI":"10.3389\/fgene.2023.1245683","article-title":"The hidden RNA code: implications of the RNA epitranscriptome in the context of viral infections","volume":"14","author":"DR Ribeiro","year":"2023","journal-title":"Front Genet"},{"issue":"3","key":"ppat.1013755.ref004","article-title":"m6 A RNA methylation: from mechanisms to therapeutic potential","volume":"40","author":"PC He","year":"2021","journal-title":"EMBO J"},{"issue":"1","key":"ppat.1013755.ref005","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1093\/toxsci\/kfab021","article-title":"Emerging Roles of N6-Methyladenosine (m6A) Epitranscriptomics in Toxicology","volume":"181","author":"E Malovic","year":"2021","journal-title":"Toxicol Sci"},{"key":"ppat.1013755.ref006","doi-asserted-by":"crossref","unstructured":"Desrosiers R, Friderici K, Rottman F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells (RNA methylation\/RNA processing\/methylnucleoside composition). 1974.","DOI":"10.1073\/pnas.71.10.3971"},{"issue":"5","key":"ppat.1013755.ref007","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1016\/j.tibs.2020.11.008","article-title":"N6-Methyladenosine Regulates Host Responses to Viral Infection","volume":"46","author":"MJ McFadden","year":"2021","journal-title":"Trends Biochem Sci"},{"issue":"7397","key":"ppat.1013755.ref008","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1038\/nature11112","article-title":"Topology of the human and mouse m6A RNA methylomes revealed by m6A-seq","volume":"485","author":"D Dominissini","year":"2012","journal-title":"Nature"},{"issue":"7","key":"ppat.1013755.ref009","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1016\/j.cell.2012.05.003","article-title":"Comprehensive analysis of mRNA methylation reveals enrichment in 3\u2019 UTRs and near stop codons","volume":"149","author":"KD Meyer","year":"2012","journal-title":"Cell"},{"issue":"3","key":"ppat.1013755.ref010","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.gpb.2017.03.002","article-title":"The RNA Modification N6-methyladenosine and Its Implications in Human Disease","volume":"15","author":"PJ Batista","year":"2017","journal-title":"Genomics Proteomics Bioinformatics"},{"issue":"9","key":"ppat.1013755.ref011","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1111\/febs.13614","article-title":"N6-methyladenosine modification in mRNA: machinery, function and implications for health and diseases","volume":"283","author":"A Maity","year":"2016","journal-title":"FEBS J"},{"issue":"7","key":"ppat.1013755.ref012","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1016\/j.cell.2017.05.045","article-title":"Dynamic RNA Modifications in Gene Expression Regulation","volume":"169","author":"IA Roundtree","year":"2017","journal-title":"Cell"},{"key":"ppat.1013755.ref013"},{"issue":"8","key":"ppat.1013755.ref014","doi-asserted-by":"crossref","first-page":"3019","DOI":"10.3390\/v6083019","article-title":"Paramyxovirus glycoprotein incorporation, assembly and budding: a three way dance for infectious particle production","volume":"6","author":"F El Najjar","year":"2014","journal-title":"Viruses"},{"key":"ppat.1013755.ref015","article-title":"Structural and molecular properties of mumps virus inclusion bodies","author":"H Katoh","year":"2024","journal-title":"Sci Adv"},{"issue":"3","key":"ppat.1013755.ref016","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1004739","article-title":"Evidence for ubiquitin-regulated nuclear and subnuclear trafficking among Paramyxovirinae matrix proteins","volume":"11","author":"M Pentecost","year":"2015","journal-title":"PLoS Pathog"},{"key":"ppat.1013755.ref017","article-title":"Paramyxovirus matrix proteins modulate host cell translation via exon-junction complex interactions in the cytoplasm","author":"C-T Hung","year":"2024","journal-title":"bioRxiv"},{"key":"ppat.1013755.ref018","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.virusres.2017.01.008","article-title":"Polymerases of paramyxoviruses and pneumoviruses","volume":"234","author":"R Fearns","year":"2017","journal-title":"Virus Res"},{"issue":"5","key":"ppat.1013755.ref019","doi-asserted-by":"crossref","DOI":"10.1371\/journal.ppat.1007749","article-title":"The R2TP complex regulates paramyxovirus RNA synthesis","volume":"15","author":"H Katoh","year":"2019","journal-title":"PLoS Pathog"},{"issue":"6","key":"ppat.1013755.ref020","doi-asserted-by":"crossref","first-page":"1460","DOI":"10.3390\/cells10061460","article-title":"New Perspectives on the Biogenesis of Viral Inclusion Bodies in Negative-Sense RNA Virus Infections","volume":"10","author":"O Dolnik","year":"2021","journal-title":"Cells"},{"issue":"5","key":"ppat.1013755.ref021","article-title":"Upon Infection, Cellular WD Repeat-Containing Protein 5 (WDR5) Localizes to Cytoplasmic Inclusion Bodies and Enhances Measles Virus Replication","volume":"92","author":"D Ma","year":"2018","journal-title":"J Virol"},{"key":"ppat.1013755.ref022","doi-asserted-by":"crossref","first-page":"109747","DOI":"10.1016\/j.vetmic.2023.109747","article-title":"Newcastle disease virus activates methylation-related enzymes to reprogram m6A methylation in infected cells","volume":"281","author":"W Yuan","year":"2023","journal-title":"Vet Microbiol"},{"issue":"1","key":"ppat.1013755.ref023","doi-asserted-by":"crossref","first-page":"4595","DOI":"10.1038\/s41467-019-12504-y","article-title":"Viral N6-methyladenosine upregulates replication and pathogenesis of human respiratory syncytial virus","volume":"10","author":"M Xue","year":"2019","journal-title":"Nat Commun"},{"issue":"4","key":"ppat.1013755.ref024","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/s41564-019-0653-9","article-title":"N6-methyladenosine modification enables viral RNA to escape recognition by RNA sensor RIG-I","volume":"5","author":"M Lu","year":"2020","journal-title":"Nat Microbiol"},{"issue":"5","key":"ppat.1013755.ref025","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1016\/j.chom.2016.09.015","article-title":"N6-Methyladenosine in Flaviviridae Viral RNA Genomes Regulates Infection","volume":"20","author":"NS Gokhale","year":"2016","journal-title":"Cell Host Microbe"},{"issue":"4","key":"ppat.1013755.ref026","doi-asserted-by":"crossref","DOI":"10.1128\/mBio.01067-21","article-title":"Methyltransferase-like 3 Modulates Severe Acute Respiratory Syndrome Coronavirus-2 RNA N6-Methyladenosine Modification and Replication","volume":"12","author":"X Zhang","year":"2021","journal-title":"mBio"},{"issue":"1","key":"ppat.1013755.ref027","doi-asserted-by":"crossref","first-page":"6350","DOI":"10.1038\/s41467-022-34209-5","article-title":"METTL3 acetylation impedes cancer metastasis via fine-tuning its nuclear and cytosolic functions","volume":"13","author":"Y Li","year":"2022","journal-title":"Nat Commun"},{"issue":"11","key":"ppat.1013755.ref028","article-title":"Ubiquitin-regulated nuclear-cytoplasmic trafficking of the Nipah virus matrix protein is important for viral budding","volume":"6","author":"YE Wang","year":"2010","journal-title":"PLoS Pathog"},{"key":"ppat.1013755.ref029","author":"M V Nachury","year":"1999"},{"issue":"6","key":"ppat.1013755.ref030","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/S0092-8674(00)80370-0","article-title":"Exportin 1 (Crm1p) is an essential nuclear export factor","volume":"90","author":"K Stade","year":"1997","journal-title":"Cell"},{"key":"ppat.1013755.ref031","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.18434","article-title":"Structural insights into the molecular mechanism of the m(6)A writer complex","volume":"5","author":"P \u015aled\u017a","year":"2016","journal-title":"Elife"},{"key":"ppat.1013755.ref032","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.92537","article-title":"The catalytic mechanism of the RNA methyltransferase METTL3","volume":"12","author":"I Corbeski","year":"2024","journal-title":"Elife"},{"issue":"2","key":"ppat.1013755.ref033","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1038\/s41590-018-0275-z","article-title":"m6A modification controls the innate immune response to infection by targeting type I interferons","volume":"20","author":"R Winkler","year":"2019","journal-title":"Nat Immunol"},{"issue":"4","key":"ppat.1013755.ref034","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41422-020-00465-7","article-title":"The m6A methylome of SARS-CoV-2 in host cells","volume":"31","author":"J Liu","year":"2021","journal-title":"Cell Res"},{"key":"ppat.1013755.ref035","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1101\/gad.348320.121","article-title":"Targeting the m6A RNA modification pathway blocks SARS-CoV-2 and HCoV-OC43 replication","volume":"35","author":"HM Burgess","year":"2021","journal-title":"Genes Dev"},{"issue":"1","key":"ppat.1013755.ref036","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1038\/s41467-021-21904-y","article-title":"N6-methyladenosine RNA modification suppresses antiviral innate sensing pathways via reshaping double-stranded RNA","volume":"12","author":"W Qiu","year":"2021","journal-title":"Nat Commun"},{"key":"ppat.1013755.ref037"},{"issue":"5","key":"ppat.1013755.ref038","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/j.chom.2016.04.002","article-title":"Posttranscriptional m(6)A Editing of HIV-1 mRNAs Enhances Viral Gene Expression","volume":"19","author":"EM Kennedy","year":"2016","journal-title":"Cell Host Microbe"},{"issue":"9","key":"ppat.1013755.ref039","doi-asserted-by":"crossref","DOI":"10.1128\/JVI.02263-16","article-title":"Viral Epitranscriptomics","volume":"91","author":"EM Kennedy","year":"2017","journal-title":"J Virol"},{"issue":"3","key":"ppat.1013755.ref040","doi-asserted-by":"crossref","DOI":"10.1016\/j.chom.2017.08.004","article-title":"Epitranscriptomic Enhancement of Influenza A Virus Gene Expression and Replication","volume":"22","author":"DG Courtney","year":"2017","journal-title":"Cell Host Microbe"},{"key":"ppat.1013755.ref041","article-title":"Measles and Nipah virus assembly: Specific lipid binding drives matrix polymerization","author":"MJ Norris","year":"2022","journal-title":"Sci Adv"},{"key":"ppat.1013755.ref042","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.virol.2021.05.014","article-title":"Amino- and carboxyl-terminal ends of the bovine parainfluenza virus type 3 matrix protein are important for virion and virus-like particle release","volume":"561","author":"H Ueda","year":"2021","journal-title":"Virology"},{"issue":"1","key":"ppat.1013755.ref043","doi-asserted-by":"crossref","first-page":"3057","DOI":"10.1038\/s41467-018-05354-7","article-title":"Viral regulation of host cell biology by hijacking of the nucleolar DNA-damage response","volume":"9","author":"SM Rawlinson","year":"2018","journal-title":"Nat Commun"},{"issue":"19","key":"ppat.1013755.ref044","doi-asserted-by":"crossref","DOI":"10.1128\/jvi.00722-22","article-title":"Nucleolar Protein Treacle Is Important for the Efficient Growth of Mumps Virus","volume":"96","author":"A Wakata","year":"2022","journal-title":"J Virol"},{"key":"ppat.1013755.ref045","article-title":"N6-Adenosine Methylation of SARS-CoV-2 5\u2019-UTR Regulates Translation","author":"A Aly","year":"2022","journal-title":"bioRxiv"},{"issue":"35","key":"ppat.1013755.ref046","doi-asserted-by":"crossref","first-page":"8829","DOI":"10.1073\/pnas.1808319115","article-title":"N6-methyladenosine modification of hepatitis B virus RNA differentially regulates the viral life cycle","volume":"115","author":"H Imam","year":"2018","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"5","key":"ppat.1013755.ref047","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/j.chom.2016.10.002","article-title":"Dynamics of Human and Viral RNA Methylation during Zika Virus Infection","volume":"20","author":"G Lichinchi","year":"2016","journal-title":"Cell Host Microbe"},{"issue":"3","key":"ppat.1013755.ref048","doi-asserted-by":"crossref","DOI":"10.1016\/j.molcel.2019.11.007","article-title":"Altered m6A Modification of Specific Cellular Transcripts Affects Flaviviridae Infection","volume":"77","author":"NS Gokhale","year":"2020","journal-title":"Mol Cell"},{"issue":"13","key":"ppat.1013755.ref049","doi-asserted-by":"crossref","DOI":"10.1016\/j.celrep.2019.02.100","article-title":"Discovery of Small Molecules that Activate RNA Methylation through Cooperative Binding to the METTL3-14-WTAP Complex Active Site","volume":"26","author":"S Selberg","year":"2019","journal-title":"Cell Rep"},{"issue":"4","key":"ppat.1013755.ref050","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1111\/1348-0421.13052","article-title":"Generation of a photocontrollable recombinant bovine parainfluenza virus type 3","volume":"67","author":"T Okura","year":"2023","journal-title":"Microbiol Immunol"},{"issue":"10","key":"ppat.1013755.ref051","doi-asserted-by":"crossref","DOI":"10.1093\/nar\/gkw104","article-title":"SRAMP: prediction of mammalian N6-methyladenosine (m6A) sites based on sequence-derived features","volume":"44","author":"Y Zhou","year":"2016","journal-title":"Nucleic Acids Res"}],"updated-by":[{"DOI":"10.1371\/journal.ppat.1013755","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000}}],"container-title":["PLOS Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013755","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T19:13:34Z","timestamp":1764962014000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.ppat.1013755"}},"subtitle":[],"editor":[{"given":"Tony","family":"Schountz,","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2025,12,1]]},"references-count":51,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12,1]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.ppat.1013755","relation":{},"ISSN":["1553-7374"],"issn-type":[{"value":"1553-7374","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,1]]}}}