title: Protein Phosphatase-1 regulates Rift Valley fever virus replication.
abstract: 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.
authors.affiliation: National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Baer
authors.affiliation: National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, USA.
authors.forename: Nazly
authors.initials: N
authors.lastname: Shafagati
authors.affiliation: National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, USA.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Benedict
authors.affiliation: Center for Sickle Cell Disease, Department of Medicine, Howard University, Washington, D.C., USA.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Ammosova
authors.affiliation: Center for Sickle Cell Disease, Department of Medicine, Howard University, Washington, D.C., USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Ivanov
authors.affiliation: National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, USA.
authors.forename: Ramin M
authors.initials: RM
authors.lastname: Hakami
authors.affiliation: Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Kaori
authors.initials: K
authors.lastname: Terasaki
authors.affiliation: Department of Microbiology and Immunology, The University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Shinji
authors.initials: S
authors.lastname: Makino
authors.affiliation: Center for Sickle Cell Disease, Department of Medicine, Howard University, Washington, D.C., USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Nekhai
authors.affiliation: National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason University, Manassas, VA, USA. Electronic address: kkehnhal@gmu.edu.
authors.forename: Kylene
authors.initials: K
authors.lastname: Kehn-Hall
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D004261:DNA Replication / Q000187:drug effects / Q000502:physiology*; D016679:Genome, Viral / Q000187:drug effects; D054884:Host-Pathogen Interactions; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D054645:Protein Phosphatase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D012367:RNA, Viral / Q000096:biosynthesis / Q000187:drug effects; D012295:Rift Valley Fever / Q000188:drug therapy / Q000821:virology; D012296:Rift Valley fever virus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000502:physiology*; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology; D014709:Vero Cells; D014764:Viral Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014774:Virulence; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
chemical_list: C000598974:1E7-03 compound; D000998:Antiviral Agents; D007211:Indoles; D034741:RNA, Small Interfering; D012367:RNA, Viral; D014764:Viral Proteins; D014508:Urea; D054645:Protein Phosphatase 1
keywords: Antiviral agent; Bunyaviridae; L polymerase; Phosphorylation; Protein phosphatase 1; Rift valley fever virus