Rift Valley fever virus NSs protein promotes post-transcriptional downregulation of protein kinase PKR and inhibits eIF2α phosphorylation

Tetsuro Ikegami, Krishna Narayanan, Sungyong Won, Wataru Kamitani, C. J. Peters, Shinji Makino

Research output: Contribution to journalArticle

148 Citations (Scopus)

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-β 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 α-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)2α 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 eIF2α accumulation. These data suggested that a combination of RVFV replication and NSs-induced host transcriptional suppression induces PKR-mediated eIF2α phosphorylation, while the NSs facilitates efficient viral translation by downregulating PKR and inhibiting PKR-mediated eIF2α 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.

Original languageEnglish (US)
Article numbere1000287
JournalPLoS Pathogens
Volume5
Issue number2
DOIs
StatePublished - Feb 2009

Fingerprint

Rift Valley fever virus
eIF-2 Kinase
Down-Regulation
Phosphorylation
Proteins
Messenger RNA
Phlebovirus
Fever
Eukaryotic Initiation Factor-2
Bunyaviridae
Amanitins
Interferon Type I
Double-Stranded RNA
Induced Abortion
RNA Viruses
Protein Biosynthesis
Dactinomycin
Livestock
Viral Proteins
Virulence Factors

ASJC Scopus subject areas

  • Microbiology
  • Parasitology
  • Virology
  • Immunology
  • Genetics
  • Molecular Biology

Cite this

Rift Valley fever virus NSs protein promotes post-transcriptional downregulation of protein kinase PKR and inhibits eIF2α phosphorylation. / Ikegami, Tetsuro; Narayanan, Krishna; Won, Sungyong; Kamitani, Wataru; Peters, C. J.; Makino, Shinji.

In: PLoS Pathogens, Vol. 5, No. 2, e1000287, 02.2009.

Research output: Contribution to journalArticle

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