Dengue virus NS5 degrades ERC1 during infection to antagonize NF-kB activation

María Mora Gonzalez Lopez Ledesma, Guadalupe Costa Navarro, Horacio M. Pallares, Ana Paletta, Federico De Maio, Nestor G. Iglesias, Leopoldo Gebhard, Santiago Oviedo Rouco, Diego S. Ojeda, Luana de Borba, María Giraldo, Ricardo Rajsbaum Gorodezky, Ana Ceballos, Nevan J. Krogan, Priya S. Shah, Andrea V. Gamarnik

Research output: Contribution to journalArticlepeer-review

Abstract

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-κB 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-κB 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.

Original languageEnglish (US)
Article numbere2220005120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number23
DOIs
StatePublished - Jun 2023
Externally publishedYes

Keywords

  • NS5 viral protein activation
  • dengue virus
  • dengue virus pathogenesis
  • evasion of innate antiviral responses
  • host–virus interactions

ASJC Scopus subject areas

  • General

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