The role of signal transducer and activator of transcription 3 in Rift Valley fever virus infection

- STAT3 is phosphorylated on tyrosine residue 705 following RVFV infection.
- Phosphorylation of STAT3 was dependent on the viral protein NSs.
- STAT3 -/- MEFs were more susceptible to RVFV-induced cell death.
- Loss of STAT3 led to an increase in pro-apoptotic gene expression.
- STAT3 functions in a pro-survival capacity by modulation of NSs localization.

Rift Valley fever (RVF) is a zoonotic disease that can cause severe illness in humans and livestock, triggering spontaneous abortion in almost 100% of pregnant ruminants. In this study, we demonstrate that signal transducer and activator of transcription 3 (STAT3) is phosphorylated on its conserved tyrosine residue (Y705) following RVFV infection. This phosphorylation was dependent on a major virulence factor, the viral nonstructural protein NSs. Loss of STAT3 had little effect on viral replication, but rather resulted in cells being more susceptible to RVFV-induced cell death. Phosphorylated STAT3 translocated to the nucleus, coinciding with inhibition of fos, jun, and nr4a2 gene expression, and the presence of STAT3 and NSs at the nr4a2 promoter. NSs was found predominantly in the cytoplasm of STAT3 null cells, indicating that STAT3 influences NSs nuclear localization. Collectively, these data demonstrate that STAT3 functions in a pro-survival capacity through modulation of NSs localization.