Antagonism of the interferon-induced OAS-RNase L pathway by murine coronavirus ns2 protein is required for virus replication and liver pathology

Cell Host Microbe. 2012 Jun 14;11(6):607-16. doi: 10.1016/j.chom.2012.04.011.


Many viruses induce hepatitis in humans, highlighting the need to understand the underlying mechanisms of virus-induced liver pathology. The murine coronavirus, mouse hepatitis virus (MHV), causes acute hepatitis in its natural host and provides a useful model for understanding virus interaction with liver cells. The MHV accessory protein, ns2, antagonizes the type I interferon response and promotes hepatitis. We show that ns2 has 2',5'-phosphodiesterase activity, which blocks the interferon inducible 2',5'-oligoadenylate synthetase (OAS)-RNase L pathway to facilitate hepatitis development. Ns2 cleaves 2',5'-oligoadenylate, the product of OAS, to prevent activation of the cellular endoribonuclease RNase L and consequently block viral RNA degradation. An ns2 mutant virus was unable to replicate in the liver or induce hepatitis in wild-type mice, but was highly pathogenic in RNase L deficient mice. Thus, RNase L is a critical cellular factor for protection against viral infection of the liver and the resulting hepatitis.

Publication types

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

MeSH terms

  • 2',5'-Oligoadenylate Synthetase / antagonists & inhibitors*
  • Adenine Nucleotides / metabolism
  • Animals
  • Endoribonucleases / antagonists & inhibitors*
  • Interferons / immunology
  • Liver / pathology
  • Liver / virology*
  • Mice
  • Murine hepatitis virus / pathogenicity*
  • Murine hepatitis virus / physiology
  • Oligoribonucleotides / metabolism
  • RNA Stability
  • RNA, Viral / metabolism
  • Viral Nonstructural Proteins / metabolism*
  • Virulence Factors / metabolism*
  • Virus Replication*


  • Adenine Nucleotides
  • Oligoribonucleotides
  • RNA, Viral
  • Viral Nonstructural Proteins
  • Virulence Factors
  • nonstructural protein, coronavirus
  • 2',5'-oligoadenylate
  • Interferons
  • 2',5'-Oligoadenylate Synthetase
  • Endoribonucleases
  • 2-5A-dependent ribonuclease