Protein Phosphatase-1 regulates Rift Valley fever virus replication

• Protein Phosphatase-1 (PP1) is a critical host factor regulating RVFV replication.
• PP1α deregulation by siRNA or 1E7-03 (small molecule inhibitor) decreases viral titers in vitro across multiple cell lines.
• 1E7-03 inhibits RVFV viral RNA production, potentially through modulation of viral N and/or L proteins.
• PP1 deregulation may prove an attractive host targeted therapeutic model, as it is a highly conserved target.

Rift Valley fever virus (RVFV), genus Phlebovirus family Bunyaviridae, is an arthropod-borne virus endemic throughout sub-Saharan Africa. Recent outbreaks have resulted in cyclic epidemics with an increasing geographic footprint, devastating both livestock and human populations. Despite being recognized as an emerging threat, relatively little is known about the virulence mechanisms and host interactions of RVFV. To date there are no FDA approved therapeutics or vaccines for RVF and there is an urgent need for their development. The Ser/Thr protein phosphatase 1 (PP1) has previously been shown to play a significant role in the replication of several viruses. Here we demonstrate for the first time that PP1 plays a prominent role in RVFV replication early on during the viral life cycle. Both siRNA knockdown of PP1α and a novel PP1-targeting small molecule compound 1E7-03, resulted in decreased viral titers across several cell lines. Deregulation of PP1 was found to inhibit viral RNA production, potentially through the disruption of viral RNA transcript/protein interactions, and indicates a potential link between PP1α and the viral L polymerase and nucleoprotein. These results indicate that PP1 activity is important for RVFV replication early on during the viral life cycle and may prove an attractive therapeutic target.