TY - JOUR
T1 - Dengue virus NS5 degrades ERC1 during infection to antagonize NF-kB activation
AU - Gonzalez Lopez Ledesma, María Mora
AU - Navarro, Guadalupe Costa
AU - Pallares, Horacio M.
AU - Paletta, Ana
AU - De Maio, Federico
AU - Iglesias, Nestor G.
AU - Gebhard, Leopoldo
AU - Rouco, Santiago Oviedo
AU - Ojeda, Diego S.
AU - de Borba, Luana
AU - Giraldo, María
AU - Rajsbaum Gorodezky, Ricardo
AU - Ceballos, Ana
AU - Krogan, Nevan J.
AU - Shah, Priya S.
AU - Gamarnik, Andrea V.
N1 - Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS.
PY - 2023/6
Y1 - 2023/6
N2 - 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.
AB - 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.
KW - NS5 viral protein activation
KW - dengue virus
KW - dengue virus pathogenesis
KW - evasion of innate antiviral responses
KW - host–virus interactions
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U2 - 10.1073/pnas.2220005120
DO - 10.1073/pnas.2220005120
M3 - Article
C2 - 37252973
AN - SCOPUS:85160594453
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 23
M1 - e2220005120
ER -