biostudies-literatureLaurent-Rolle MNIAID NIH HHSPHS HHS314-327https://www.ebi.ac.uk/biostudies/studies/S-EPMC4176702biostudies-literatureUnknown16(3)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.Cell host & microbeThe interferon signaling antagonist function of yellow fever virus NS5 protein is activated by type I interferon.PMC4176702U54AI057158U54 AI057158FAI077333AMorrison JPisanelli GtenOever BRMacleod JMLGarcia-Sastre ARajsbaum RLaurent-Rolle MMiorin LMartinez CAyllon JPham AfalseThe interferon signaling antagonist function of yellow fever virus NS5 protein is activated by type I interferon.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.2014-01-01T00:00:00Z2014 Sep2024-11-19T19:34:01.877Z2019-03-27T01:36:33ZS-EPMC41767022521107410.1016/j.chom.2014.07.015