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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,6,6]]},"abstract":"<jats:p>Dengue virus (DENV) is the most important human virus transmitted by mosquitos. Dengue pathogenesis is characterized by a large induction of proinflammatory cytokines. This cytokine induction varies among the four DENV serotypes (DENV1 to 4) and poses a challenge for live DENV vaccine design. Here, we identify a viral mechanism to limit NF-\u03baB activation and cytokine secretion by the DENV protein NS5. Using proteomics, we found that NS5 binds and degrades the host protein ERC1 to antagonize NF-\u03baB activation, limit proinflammatory cytokine secretion, and reduce cell migration. We found that ERC1 degradation involves unique properties of the methyltransferase domain of NS5 that are not conserved among the four DENV serotypes. By obtaining chimeric DENV2 and DENV4 viruses, we map the residues in NS5 for ERC1 degradation, and generate recombinant DENVs exchanging serotype properties by single amino acid substitutions. This work uncovers a function of the viral protein NS5 to limit cytokine production, critical to dengue pathogenesis. Importantly, the information provided about the serotype-specific mechanism for counteracting the antiviral response can be applied to improve live attenuated vaccines.<\/jats:p>","DOI":"10.1073\/pnas.2220005120","type":"journal-article","created":{"date-parts":[[2023,5,30]],"date-time":"2023-05-30T13:31:38Z","timestamp":1685453498000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":36,"title":["Dengue virus NS5 degrades ERC1 during infection to antagonize NF-kB activation"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2189-8388","authenticated-orcid":false,"given":"Mar\u00eda Mora","family":"Gonzalez Lopez Ledesma","sequence":"first","affiliation":[{"name":"Fundaci\u00f3n Instituto Leloir-CONICET, Buenos Aires C1405, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guadalupe","family":"Costa Navarro","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n 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Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nestor G.","family":"Iglesias","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Instituto Leloir-CONICET, Buenos Aires C1405, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leopoldo","family":"Gebhard","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Instituto Leloir-CONICET, Buenos Aires C1405, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Santiago","family":"Oviedo Rouco","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Instituto Leloir-CONICET, Buenos Aires C1405, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego S.","family":"Ojeda","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Instituto Leloir-CONICET, Buenos Aires C1405, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5918-0156","authenticated-orcid":false,"given":"Luana","family":"de Borba","sequence":"additional","affiliation":[{"name":"Fundaci\u00f3n Instituto Leloir-CONICET, Buenos Aires C1405, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Giraldo","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5058-5444","authenticated-orcid":false,"given":"Ricardo","family":"Rajsbaum","sequence":"additional","affiliation":[{"name":"Department of Medicine, Center for Virus-Host-Innate-Immunity, Rutgers Biomedical and Health Sciences, Newark, NJ 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Samsa Dengue virus capsid protein usurps lipid droplets for viral particle formation. PLoS Pathog. 5 e1000632 (2009). e1000632","DOI":"10.1371\/journal.ppat.1000632"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201805002"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jmb.2021.167228"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1089\/jir.2011.0028"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M114.584466"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.92424"},{"key":"e_1_3_4_28_2","doi-asserted-by":"crossref","unstructured":"K. M. Soo B. Khalid S. M. Ching H. Y. Chee Meta-analysis of dengue severity during infection by different dengue virus serotypes in primary and secondary infections. 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