Rift Valley fever virus NSs inhibits host transcription independently of the degradation of dsRNA-dependent protein kinase PKR

Virology. 2013 Jan 20;435(2):415-24. doi: 10.1016/j.virol.2012.09.031. Epub 2012 Oct 12.

Abstract

Rift Valley fever virus (RVFV) encodes one major virulence factor, the NSs protein. NSs suppresses host general transcription, including interferon (IFN)-β mRNA synthesis, and promotes degradation of the dsRNA-dependent protein kinase (PKR). We generated a novel RVFV mutant (rMP12-NSsR173A) specifically lacking the function to promote PKR degradation. rMP12-NSsR173A infection induces early phosphorylation of eIF2α through PKR activation, while retaining the function to inhibit host general transcription including IFN-β gene inhibition. MP-12 NSs but not R173A NSs binds to wt PKR. R173A NSs formed filamentous structure in nucleus in a mosaic pattern, which was distinct from MP-12 NSs filament pattern. Due to early phosphorylation of eIF2α, rMP12-NSsR173A could not efficiently accumulate viral proteins. Our results suggest that NSs-mediated host general transcription suppression occurs independently of PKR degradation, while the PKR degradation is important to inhibit the phosphorylation of eIF2α in infected cells undergoing host general transcription suppression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Chlorocebus aethiops
  • Eukaryotic Initiation Factor-2 / genetics
  • Eukaryotic Initiation Factor-2 / metabolism
  • Fibroblasts / virology
  • HEK293 Cells
  • Humans
  • Mice
  • Mutation
  • Phosphorylation
  • RNA, Double-Stranded / genetics
  • RNA, Double-Stranded / metabolism*
  • Rift Valley fever virus / genetics
  • Rift Valley fever virus / pathogenicity*
  • Vero Cells
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism*
  • Viral Proteins / genetics
  • Viral Proteins / metabolism
  • Virus Replication
  • eIF-2 Kinase / metabolism*

Substances

  • Eukaryotic Initiation Factor-2
  • RNA, Double-Stranded
  • Viral Nonstructural Proteins
  • Viral Proteins
  • eIF-2 Kinase