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

Abstract
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.
AuthorsLing Zhao, Babal K Jha, Ashley Wu, Ruth Elliott, John Ziebuhr, Alexander E Gorbalenya, Robert H Silverman, Susan R Weiss
JournalCell host & microbe (Cell Host Microbe) Vol. 11 Issue 6 Pg. 607-16 (Jun 14 2012) ISSN: 1934-6069 [Electronic] United States
PMID22704621 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2012 Elsevier Inc. All rights reserved.
Chemical References
  • 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
Topics
  • 2',5'-Oligoadenylate Synthetase (antagonists & inhibitors)
  • Adenine Nucleotides (metabolism)
  • Animals
  • Endoribonucleases (antagonists & inhibitors)
  • Interferons (immunology)
  • Liver (pathology, virology)
  • Mice
  • Murine hepatitis virus (pathogenicity, physiology)
  • Oligoribonucleotides (metabolism)
  • RNA Stability
  • RNA, Viral (metabolism)
  • Viral Nonstructural Proteins (metabolism)
  • Virulence Factors (metabolism)
  • Virus Replication

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