TY - JOUR
T1 - The interferon signaling antagonist function of yellow fever virus NS5 protein is activated by type i interferon
AU - Laurent-Rolle, Maudry
AU - Morrison, Juliet
AU - Rajsbaum, Ricardo
AU - Macleod, Jesica M.Levingston
AU - Pisanelli, Giuseppe
AU - Pham, Alissa
AU - Ayllon, Juan
AU - Miorin, Lisa
AU - Martínez-Romero, Carles
AU - Tenoever, Benjamin R.
AU - García-Sastre, Adolfo
N1 - Publisher Copyright:
© 2014 Elsevier Inc.
PY - 2014/9/10
Y1 - 2014/9/10
N2 - 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.
AB - 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.
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U2 - 10.1016/j.chom.2014.07.015
DO - 10.1016/j.chom.2014.07.015
M3 - Article
C2 - 25211074
AN - SCOPUS:84907700872
SN - 1931-3128
VL - 16
SP - 314
EP - 327
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 3
ER -