{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T17:31:07Z","timestamp":1786469467388,"version":"build-2736575974"},"reference-count":43,"publisher":"American Society for Microbiology","issue":"8","license":[{"start":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T00:00:00Z","timestamp":1693440000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2023,8,31]],"date-time":"2023-08-31T00:00:00Z","timestamp":1693440000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"funder":[{"name":"Gouvernement du Canada | Canadian Institutes of Health Research","award":["PJT-156351"],"award-info":[{"award-number":["PJT-156351"]}]},{"name":"Gouvernement du Canada | Canadian Institutes of Health Research","award":["PJT-173318"],"award-info":[{"award-number":["PJT-173318"]}]},{"name":"Gouvernement du Canada | Canadian Institutes of Health Research","award":["FDN-148408"],"award-info":[{"award-number":["FDN-148408"]}]},{"name":"Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada","award":["RGPIN-2017-04515"],"award-info":[{"award-number":["RGPIN-2017-04515"]}]},{"name":"Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada","award":["RGPIN-2022-02979"],"award-info":[{"award-number":["RGPIN-2022-02979"]}]},{"name":"Gouvernement du Canada | Natural Sciences and Engineering Research Council of Canada","award":["PGSD"],"award-info":[{"award-number":["PGSD"]}]}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2023,8,31]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            Viruses have evolved diverse strategies to evade the host innate immune response and promote infection. The retinoic acid-inducible gene I (RIG-I)-like receptors RIG-I and MDA5 are antiviral factors that sense viral RNA and trigger downstream signal via mitochondrial antiviral-signaling protein (MAVS) to activate type I interferon expression. 14-3-3\u03b5 is a key component of the RIG-I translocon complex that interacts with MAVS at the mitochondrial membrane; however, the exact role of 14-3-3\u03b5 in this pathway is not well understood. In this study, we demonstrate that 14-3-3\u03b5 is a direct substrate of both the poliovirus and coxsackievirus B3 (CVB3) 3C proteases (3C\n            <jats:sup>pro<\/jats:sup>\n            ) and that it is cleaved at Q236\u2193G237, resulting in the generation of N- and C-terminal fragments of 27.0 and 2.1 kDa, respectively. While the exogenous expression of wild-type 14-3-3\u03b5 enhances\n            <jats:italic>IFNB<\/jats:italic>\n            mRNA production during poly(I:C) stimulation, expression of the truncated N-terminal fragment does not. The N-terminal 14-3-3\u03b5 fragment does not interact with RIG-I in co-immunoprecipitation assays, nor can it facilitate RIG-I translocation to the mitochondria. Probing the intrinsically disordered C-terminal region identifies key residues responsible for the interaction between 14-3-3\u03b5 and RIG-I. Finally, overexpression of the N-terminal fragment promotes CVB3 infection in mammalian cells. The strategic enterovirus 3C\n            <jats:sup>pro<\/jats:sup>\n            -mediated cleavage of 14-3-3\u03b5 antagonizes RIG-I signaling by disrupting critical interactions within the RIG-I translocon complex, thus contributing to evasion of the host antiviral response.\n          <\/jats:p>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>Host antiviral factors work to sense virus infection through various mechanisms, including a complex signaling pathway known as the retinoic acid-inducible gene I (RIG-I)-like receptor pathway. This pathway drives the production of antiviral molecules known as interferons, which are necessary to establish an antiviral state in the cellular environment. Key to this antiviral signaling pathway is the small chaperone protein 14-3-3\u03b5, which facilitates the delivery of a viral sensor protein, RIG-I, to the mitochondria. In this study, we show that the enteroviral 3C protease cleaves 14-3-3\u03b5 during infection, rendering it incapable of facilitating this antiviral response. We also find that the resulting N-terminal cleavage fragment dampens RIG-I signaling and promotes virus infection. Our findings reveal a novel viral strategy that restricts the antiviral host response and provides insights into the mechanisms underlying 14-3-3\u03b5 function in RIG-I antiviral signaling.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jvi.00604-23","type":"journal-article","created":{"date-parts":[[2023,8,9]],"date-time":"2023-08-09T13:00:25Z","timestamp":1691586025000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":18,"title":["Cleavage of 14-3-3\u03b5 by the enteroviral 3C protease dampens RIG-I-mediated antiviral signaling"],"prefix":"10.1128","volume":"97","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5063-738X","authenticated-orcid":true,"given":"Daniel D. 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