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These lesions can persist for long periods without an effective clearance response from the host. MCV, like all poxviruses, encodes multiple known immunosuppressive proteins which target innate immune signalling pathways involved in viral nucleic acid sensing, interferon production and inflammation which should trigger antiviral immunity leading to clearance. Two major families of transcription factors responsible for driving the immune response to viruses are the NF-\u03baB and the interferon regulatory factor (IRF) families. While NF-\u03baB broadly drives pro-inflammatory gene expression and IRFs chiefly drive interferon induction, both collaborate in transactivating many of the same genes in a concerted immune response to viral infection. Here, we report that the MCV protein MC089 specifically inhibits IRF activation from both DNA- and RNA-sensing pathways, making it the first characterized MCV inhibitor to selectively target IRF activation to date. MC089 interacts with proteins required for IRF activation, namely IKK\u03b5, TBKBP1 and NAP1. Additionally, MC089 targets RNA sensing by associating with the RNA-sensing adaptor protein mitochondrial antiviral-signalling protein on mitochondria. MC089 displays specificity in its inhibition of IRF3 activation by suppressing immunostimulatory nucleic acid-induced serine 396 phosphorylation without affecting the phosphorylation of serine 386. The selective interaction of MC089 with IRF-regulatory proteins and site-specific inhibition of IRF3 phosphorylation may offer a tool to provide novel insights into the biology of IRF3 regulation.<\/jats:p>","DOI":"10.1099\/jgv.0.002015","type":"journal-article","created":{"date-parts":[[2024,8,21]],"date-time":"2024-08-21T22:27:28Z","timestamp":1724279248000},"source":"Crossref","is-referenced-by-count":1,"title":["Molluscum contagiosum virus protein MC089 inhibits interferon regulatory factor 3 activation"],"prefix":"10.1099","volume":"105","author":[{"given":"Mariya","family":"Al Hamrashdi","sequence":"first","affiliation":[{"name":"Trinity Health Kidney Centre, Trinity Translational Medicine Institute, Trinity College Dublin, St. James\u2019 Hospital Campus, Dublin, Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carla","family":"Sanchez Perez","sequence":"additional","affiliation":[{"name":"Trinity Health Kidney Centre, Trinity Translational Medicine 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