The interferon signaling antagonist function of yellow fever virus NS5 protein is activated by type i interferon

Maudry Laurent-Rolle, Juliet Morrison, Ricardo Rajsbaum, Jesica M.Levingston Macleod, Giuseppe Pisanelli, Alissa Pham, Juan Ayllon, Lisa Miorin, Carles Martínez-Romero, Benjamin R. Tenoever, Adolfo García-Sastre

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

To successfully establish infection, flaviviruses have to overcome the antiviral state induced by type I interferon (IFN-I). The nonstructural NS5 proteins of several flaviviruses antagonize IFN-I signaling. Here we show that yellow fever virus (YFV) inhibits IFN-I signaling through a unique mechanism that involves binding of YFV NS5 to the IFN-activated transcription factor STAT2 only in cells that have been stimulated with IFN-I. This NS5-STAT2 interaction requires IFN-I-induced tyrosine phosphorylation of STAT1 and the K63-linked polyubiquitination at a lysine in the N-terminal region of YFV NS5. We identified TRIM23 as the E3 ligase that interacts with and polyubiquitinates YFV NS5 to promote its binding to STAT2 and trigger IFN-I signaling inhibition. Our results demonstrate the importance of YFV NS5 in overcoming the antiviral action of IFN-I and offer a unique example of a viral protein that is activated by the same host pathway that it inhibits.

Original languageEnglish (US)
Pages (from-to)314-327
Number of pages14
JournalCell Host and Microbe
Volume16
Issue number3
DOIs
StatePublished - Sep 10 2014
Externally publishedYes

ASJC Scopus subject areas

  • Parasitology
  • Microbiology
  • Virology

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    Laurent-Rolle, M., Morrison, J., Rajsbaum, R., Macleod, J. M. L., Pisanelli, G., Pham, A., Ayllon, J., Miorin, L., Martínez-Romero, C., Tenoever, B. R., & García-Sastre, A. (2014). The interferon signaling antagonist function of yellow fever virus NS5 protein is activated by type i interferon. Cell Host and Microbe, 16(3), 314-327. https://doi.org/10.1016/j.chom.2014.07.015