title: Rift Valley fever virus NSs protein promotes post-transcriptional downregulation of protein kinase PKR and inhibits eIF2alpha phosphorylation.
abstract: Rift Valley fever virus (RVFV) (genus Phlebovirus, family Bunyaviridae) is a negative-stranded RNA virus with a tripartite genome. RVFV is transmitted by mosquitoes and causes fever and severe hemorrhagic illness among humans, and fever and high rates of abortions in livestock. A nonstructural RVFV NSs protein inhibits the transcription of host mRNAs, including interferon-beta mRNA, and is a major virulence factor. The present study explored a novel function of the RVFV NSs protein by testing the replication of RVFV lacking the NSs gene in the presence of actinomycin D (ActD) or alpha-amanitin, both of which served as a surrogate of the host mRNA synthesis suppression function of the NSs. In the presence of the host-transcriptional inhibitors, the replication of RVFV lacking the NSs protein, but not that carrying NSs, induced double-stranded RNA-dependent protein kinase (PKR)-mediated eukaryotic initiation factor (eIF)2alpha phosphorylation, leading to the suppression of host and viral protein translation. RVFV NSs promoted post-transcriptional downregulation of PKR early in the course of the infection and suppressed the phosphorylated eIF2alpha accumulation. These data suggested that a combination of RVFV replication and NSs-induced host transcriptional suppression induces PKR-mediated eIF2alpha phosphorylation, while the NSs facilitates efficient viral translation by downregulating PKR and inhibiting PKR-mediated eIF2alpha phosphorylation. Thus, the two distinct functions of the NSs, i.e., the suppression of host transcription, including that of type I interferon mRNAs, and the downregulation of PKR, work together to prevent host innate antiviral functions, allowing efficient replication and survival of RVFV in infected mammalian hosts.
authors.affiliation: Department of Microbiology and Immunology, The University of Texas Medical Branch at Galveston, Galveston, TX, USA. teikegam@utmb.edu
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ikegami
authors.forename: Krishna
authors.initials: K
authors.lastname: Narayanan
authors.forename: Sungyong
authors.initials: S
authors.lastname: Won
authors.forename: Wataru
authors.initials: W
authors.lastname: Kamitani
authors.forename: C J
authors.initials: CJ
authors.lastname: Peters
authors.forename: Shinji
authors.initials: S
authors.lastname: Makino
mesh_terms: D000818:Animals; D002522:Chlorocebus aethiops; D003609:Dactinomycin / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D055786:Gene Knockout Techniques; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000502:physiology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000378:metabolism; D012296:Rift Valley fever virus / Q000235:genetics / Q000254:growth & development / Q000472:pathogenicity* / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D037521:Virulence Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014779:Virus Replication; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D015852:Eukaryotic Initiation Factor-2; D019384:Nucleic Acid Synthesis Inhibitors; D012333:RNA, Messenger; D017361:Viral Nonstructural Proteins; D037521:Virulence Factors; D003609:Dactinomycin; D019892:eIF-2 Kinase