Mutual antagonism between the Ebola virus VP35 protein and the RIG-I activator PACT determines infection outcome

Cell Host Microbe. 2013 Jul 17;14(1):74-84. doi: 10.1016/j.chom.2013.06.010.

Abstract

The cytoplasmic pattern recognition receptor RIG-I is activated by viral RNA and induces type I IFN responses to control viral replication. The cellular dsRNA binding protein PACT can also activate RIG-I. To counteract innate antiviral responses, some viruses, including Ebola virus (EBOV), encode proteins that antagonize RIG-I signaling. Here, we show that EBOV VP35 inhibits PACT-induced RIG-I ATPase activity in a dose-dependent manner. The interaction of PACT with RIG-I is disrupted by wild-type VP35, but not by VP35 mutants that are unable to bind PACT. In addition, PACT-VP35 interaction impairs the association between VP35 and the viral polymerase, thereby diminishing viral RNA synthesis and modulating EBOV replication. PACT-deficient cells are defective in IFN induction and are insensitive to VP35 function. These data support a model in which the VP35-PACT interaction is mutually antagonistic and plays a fundamental role in determining the outcome of EBOV infection.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Motifs
  • Cell Line
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / antagonists & inhibitors
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • Ebolavirus / chemistry
  • Ebolavirus / genetics
  • Ebolavirus / metabolism*
  • Hemorrhagic Fever, Ebola / enzymology
  • Hemorrhagic Fever, Ebola / genetics
  • Hemorrhagic Fever, Ebola / metabolism*
  • Hemorrhagic Fever, Ebola / virology
  • Humans
  • Protein Binding
  • RNA, Viral / genetics
  • RNA, Viral / metabolism
  • RNA-Binding Proteins / antagonists & inhibitors
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism*
  • Viral Regulatory and Accessory Proteins / antagonists & inhibitors
  • Viral Regulatory and Accessory Proteins / chemistry
  • Viral Regulatory and Accessory Proteins / genetics
  • Viral Regulatory and Accessory Proteins / metabolism*

Substances

  • PRKRA protein, human
  • RNA, Viral
  • RNA-Binding Proteins
  • VP35 protein, filovirus
  • Viral Regulatory and Accessory Proteins
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases