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 Martı´nez-Romero, Benjamin R. tenOever and AdolfoGarcı´a-Sastre

Cell Host & Microbe 16, 314–327, September 10, 2014

Speaker: Chia-Yi Hung (洪嘉依)                              Time: 14:00~15:00, June 3, 2015

Commentator: Dr. Chia-Yi Yu (余佳益 老師)         Place: Room 601

Abstract:

Type I interferons (IFN-I) are responsible for activation of a large group of genes, which are involved in host resistance to viral infection. The flaviviruses such as dengue virus (DENV), West Nile virus (WNV) and yellow fever virus (YFV) cause severe infections in the world. In order to establish successful infection, flaviviruses must overcome the host defensive strategy like type I interferons. The nonstructural NS5 proteins of several flaviviruses except for YFV have ability to antagonize IFN-I signaling. Considering that DENV was known to antagonize IFN-I signaling and its NS5 protein had previously been identified as IFN-I signaling antagonist (1), the authors wanted to know whether YFV also possesses these abilities. In this study, they discovered that YFV NS5 inhibits IFN-I signaling by binding to STAT2 and prevents IFN-stimulated gene factor 3 (ISGF3) engagement with IFN-I-stimulated response elements (ISREs). Furthermore, they found that the N-terminus especially a lysine residue within the first ten amino acids of YFV NS5 is required for IFN-I signaling antagonism. They also identified that a lysine in the first ten amino acids of the protein was required for interaction of YFV NS5 and STAT2 as well as the K63-linked association of YFV NS5 with ubiquitin. In addition, IFN-I induced tyrosine phosphorylation of STAT1 is also required for NS5-STAT2 interaction, most likely by promoting conformational changes in STAT2 that trigger its association with ubiquitinated NS5. This study offer a unique example of a viral IFN-I signaling antagonist that is itself activated by IFN-I.

References:

1. Joseph Ashour, Maudry Laurent-Rolle, Pei-Yong Shi, and Adolfo García-Sastre (2009) NS5 of Dengue Virus Mediates STAT2 Binding and Degradation. J Virol. 83:5408-5418