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Here, we investigated how the integrated stress response (ISR), which promotes translational arrest by eIF2\u0251 phosphorylation (p-eIF2\u0251), regulates flavivirus replication. During dengue virus (DENV) and Zika virus (ZIKV) infection, eIF2\u0251 phosphorylation peaked at 24 hours post-infection and was dependent on protein kinase RNA-activated (PKR) but not type I interferon. The ISR is activated downstream of p-eIF2\u03b1 during infection with either virus, but translation arrest only occurred following DENV4 infection. Despite this difference, both DENV4 and ZIKV replications were impaired in cells lacking PKR, independent of type I interferon\/NF-kB signaling or cell viability. By using a ZIKV 5\u2032-untranslated region (UTR) reporter system as a model, we found that this region of the genome is sufficient to promote an enhancement of viral mRNA translation in the presence of an active ISR. Together, we provide evidence that flaviviruses escape ISR translational arrest and co-opt this response to increase viral replication.<\/jats:p>\n                  <jats:sec>\n                    <jats:title>IMPORTANCE<\/jats:title>\n                    <jats:p>One of the fundamental features that make viruses intracellular parasites is the necessity to use cellular translational machinery. Hence, this is a crucial checkpoint for controlling infections. Here, we show that dengue and Zika viruses, responsible for nearly 400 million infections every year worldwide, explore such control for optimal replication. Using immunocompetent cells, we demonstrate that arrest of protein translations happens after sensing of dsRNA and that the information required to avoid this blocking is contained in viral 5\u2032-UTR. Our work, therefore, suggests that the non-canonical translation described for these viruses is engaged when the intracellular stress response is activated.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1128\/mbio.00934-23","type":"journal-article","created":{"date-parts":[[2023,9,21]],"date-time":"2023-09-21T09:05:02Z","timestamp":1695287102000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":25,"title":["PKR-mediated stress response enhances dengue and Zika virus replication"],"prefix":"10.1128","volume":"14","author":[{"given":"Taissa","family":"Ricciardi-Jorge","sequence":"first","affiliation":[{"name":"Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina (UFSC) , Florian\u00f3polis, Brazil"},{"name":"The Pirbright Institute , Woking, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edroaldo Lummertz","family":"da Rocha","sequence":"additional","affiliation":[{"name":"Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina (UFSC) , Florian\u00f3polis, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgar","family":"Gonzalez-Kozlova","sequence":"additional","affiliation":[{"name":"Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina (UFSC) , Florian\u00f3polis, Brazil"},{"name":"Icahn School of Medicine , New York, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela Flavia","family":"Rodrigues-Luiz","sequence":"additional","affiliation":[{"name":"Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina (UFSC) , Florian\u00f3polis, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian J.","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Cambridge , Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trevor","family":"Sweeney","sequence":"additional","affiliation":[{"name":"The Pirbright Institute , Woking, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nerea","family":"Irigoyen","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Cambridge , Cambridge, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6773-9334","authenticated-orcid":false,"given":"Daniel Santos","family":"Mansur","sequence":"additional","affiliation":[{"name":"Departamento de Microbiologia, Imunologia e Parasitologia, Universidade Federal de Santa Catarina (UFSC) , Florian\u00f3polis, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.mi.44.100190.003245"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00986-10"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.80.6.2976-2986.2006"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.00459-19"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.01998-20"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.3390\/v9090262"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/mBio.02150-16"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-012-1252-6"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201642195"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1042\/BST20060007"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.21.15.5018-5030.2001"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2838"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007287"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00313-19"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007261"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chom.2018.05.005"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","unstructured":"Espada CE da Rocha EL Ricciardi-Jorge T dos Santos AA Soares ZG Dias GBM de Oliveira Patricio D Gonzalez-Kozlova E dos Santos PF Bordignon J Sanford TJ Fajardo T Sweeney TR B\u00e1fica A Mansur DS . 2019. 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