Antagonism of the interferon-induced OAS-RNase L pathway by murine coronavirus ns2 protein is required for virus replication and liver pathology.
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.
Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Ling
L
Zhao
Babal K
BK
Jha
Ashley
A
Wu
Ruth
R
Elliott
John
J
Ziebuhr
Alexander E
AE
Gorbalenya
Robert H
RH
Silverman
Susan R
SR
Weiss
D015088:2',5'-Oligoadenylate Synthetase / Q000037:antagonists & inhibitors*; D000227:Adenine Nucleotides / Q000378:metabolism; D000818:Animals; D004722:Endoribonucleases / Q000037:antagonists & inhibitors*; D007372:Interferons / Q000276:immunology; D008099:Liver / Q000473:pathology / Q000821:virology*; D051379:Mice; D006517:Murine hepatitis virus / Q000472:pathogenicity* / Q000502:physiology; D009843:Oligoribonucleotides / Q000378:metabolism; D020871:RNA Stability; D012367:RNA, Viral / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D037521:Virulence Factors / Q000378:metabolism*; D014779:Virus Replication
D000227:Adenine Nucleotides; D009843:Oligoribonucleotides; D012367:RNA, Viral; D017361:Viral Nonstructural Proteins; D037521:Virulence Factors; C087633:nonstructural protein, coronavirus; C023505:2',5'-oligoadenylate; D007372:Interferons; D015088:2',5'-Oligoadenylate Synthetase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease