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The roles of viral proteins in these processes have been studied mostly <jats:italic><jats:italic>in vitro<\/jats:italic><\/jats:italic>, by ectopic overexpression, or by surrogate infection systems, all of which have shortcomings. Here, we replace the essential 2A cleavage site at the P1-P2 junction with an internal ribosome entry site (IRES), 3CD cleavage site, or T2A sequence, allowing us to catalytically inactivate 2A<jats:sup>pro<\/jats:sup> in the virus context. Viruses with an inactive 2A<jats:sup>pro<\/jats:sup> are hampered in replication in cell lines and are severely attenuated in a Coxsackievirus B3 (CVB3) mouse pancreatitis infection model. We show that 2A<jats:sup>pro<\/jats:sup> is essential for disturbing nucleocytoplasmic transport, shutting down host mRNA translation, suppressing stress granule formation, suppressing the induction of the IFN response, and overcoming IFN-induced restriction factors. Moreover, using an advanced single-molecule live cell imaging approach, we reveal that 2A<jats:sup>pro<\/jats:sup> is important for the initial round of replication of the incoming viral RNA, which is a bottleneck for efficient infection. Thus, 2A<jats:sup>pro<\/jats:sup> plays a critical role in subverting antiviral responses and establishing a favorable environment to expedite enterovirus replication.<\/jats:p>","DOI":"10.1371\/journal.ppat.1013443","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T17:40:07Z","timestamp":1756402807000},"page":"e1013443","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["The multifaceted role of the viral 2A protease in enterovirus replication and antagonism of host antiviral responses"],"prefix":"10.1371","volume":"21","author":[{"given":"Jelle G.","family":"Schipper","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiara","family":"Aloise","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sereina O.","family":"Sutter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marleen","family":"Zwaagstra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arno L.W.","family":"van Vliet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rana","family":"Abdelnabi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bob","family":"Ignacio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimberly M.","family":"Bonger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"Roelofs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith M.A.","family":"van den Brand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard W.","family":"Wubbolts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas J.M.","family":"Bruurs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrik Jan","family":"Thibaut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johan","family":"Neyts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marvin E.","family":"Tanenbaum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5800-749X","authenticated-orcid":true,"given":"Frank J. 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