A SAP30 complex inhibits IFN-beta expression in Rift Valley fever virus infected cells

PLoS Pathog. 2008 Jan;4(1):e13. doi: 10.1371/journal.ppat.0040013.

Abstract

Rift Valley fever virus (RVFV) nonstructural protein NSs acts as the major determinant of virulence by antagonizing interferon beta (IFN-beta) gene expression. We demonstrate here that NSs interacts with the host protein SAP30, which belongs to Sin3A/NCoR/HDACs repressor complexes and interacts with the transcription factor YY1 that regulates IFN-beta gene expression. Using confocal microscopy and chromatin immunoprecipitation, we show that SAP30, YY1, and Sin3A-associated corepressor factors strongly colocalize with nuclear NSs filaments and that NSs, SAP30 and Sin3A-associated factors are recruited on the IFN-beta promoter through YY1, inhibiting CBP recruitment, histone acetylation, and transcriptional activation. To ascertain the role of SAP30, we produced, by reverse genetics, a recombinant RVFV in which the interacting domain in NSs was deleted. The virus was unable to inhibit the IFN response and was avirulent for mice. We discuss here the strategy developed by the highly pathogenic RVFV to evade the host antiviral response, affecting nuclear organization and IFN-beta promoter chromatin structure.

Publication types

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

MeSH terms

  • Animals
  • Cell Nucleus / metabolism
  • Cells, Cultured
  • Chlorocebus aethiops
  • Gene Expression Regulation, Viral
  • Histone Deacetylases / genetics
  • Histone Deacetylases / metabolism*
  • Interferon-beta / genetics
  • Interferon-beta / metabolism*
  • Mice
  • Microscopy, Confocal
  • Mutation
  • Repressor Proteins / metabolism*
  • Rift Valley fever virus / physiology*
  • Two-Hybrid System Techniques
  • Vero Cells
  • Viral Nonstructural Proteins / genetics
  • Viral Nonstructural Proteins / metabolism*
  • Virulence
  • YY1 Transcription Factor / metabolism*

Substances

  • Repressor Proteins
  • SIN3A transcription factor
  • Sap30 protein, mouse
  • Viral Nonstructural Proteins
  • YY1 Transcription Factor
  • Yy1 protein, mouse
  • Interferon-beta
  • Histone Deacetylases