{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:09:37Z","timestamp":1787724577846,"version":"build-2784847793"},"reference-count":56,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T00:00:00Z","timestamp":1755043200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Major Scientific and Technological Project of Henan Province","award":["221100110600"],"award-info":[{"award-number":["221100110600"]}]},{"DOI":"10.13039\/501100006407","name":"Natural Science Foundation of Henan Province","doi-asserted-by":"publisher","award":["232300421160"],"award-info":[{"award-number":["232300421160"]}],"id":[{"id":"10.13039\/501100006407","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Outstanding Young Scientists of Henan Agricultural University","award":["30500690"],"award-info":[{"award-number":["30500690"]}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>The ERK-mediated phosphorylation of the core m<jats:sup>6<\/jats:sup>A methyltransferase METTL3 has been linked to the regulation of embryonic stem cell differentiation and tumorigenesis. However, its role in the antiviral innate immune response remains unclear. In this study, we found that during infection with the prototypical alpha-herpesvirus Pseudorabies virus (PRV), ERK2 protein expression increased significantly, while METTL3 expression decreased both <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>. Overexpressing ERK2 and METTL3 effectively reduced PRV replication, while their knockdown promoted viral replication. The C-terminal domain and enzymatic active site of METTL3 were essential for suppressing viral replication. Mechanistically, ERK2 phosphorylates METTL3 at serine 43. We further found that ERK2-mediated phosphorylation at this site enhances the type I interferon (IFN-\u03b2)-induced innate immune response by activating the NF-\u03baB pathway, increasing m<jats:sup>6<\/jats:sup>A modification, and elevating protein translation levels. Notably, combined treatment with ERK2 and METTL3 inhibitors promoted viral replication, intensified organ damage, and hastened mortality in mice by suppressing IFN-\u03b2 production. In conclusion, our study reveals phosphorylation-dependent crosstalk between MAPK signaling and the m<jats:sup>6<\/jats:sup>A machinery in antiviral defense, identifies Ser43 as a functional hotspot for METTL3\u2019s immunoregulatory activity, and indicates that the ERK-METTL3 axis is a novel regulator of the antiviral innate immune response during alpha-herpesvirus infection. This work establishes a paradigm shift in understanding how post-translational modifications of RNA-modifying enzymes orchestrate antiviral immunity, providing new avenues for host-directed antiviral strategies.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013234","type":"journal-article","created":{"date-parts":[[2025,8,13]],"date-time":"2025-08-13T18:12:14Z","timestamp":1755108734000},"page":"e1013234","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["ERK-METTL3 axis acts as a novel regulator of antiviral innate immunity combating pseudorabies virus 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