The Role of NS5 Protein in Determination of Host Cell Range for Yellow Fever Virus.

Yellow fever virus (YFV) tropism is restricted to human and nonhuman primates. The nonstructural protein 5 (NS5) protein of YFV binds to primate signal transducer and activator of transcription 2 (STAT2) and antagonizes interferon (IFN) signaling. However, YFV NS5 is unable to bind mouse STAT2 and antagonize murine IFN signaling. A similar observation has been made with the NS5 protein of both dengue virus (DENV) and Zika virus (ZIKV). However, the key difference between the NS5 protein of YFV and those of DENV and ZIKV is that YFV NS5 binds human STAT2 in an IFN-dependent manner. In human cells, IFN-I treatment induces K63-linked ubiquitination on lysine (K) 6 of YFV NS5, which is required for binding human STAT2. This IFN-induced ubiquitination of YFV NS5 is absent in murine cells resulting in the lack of binding of YFV NS5 and human STAT2 in murine cells. This highlights the importance of YFV NS5 ubiquitination in determining the host cell range for YFV.