Lineage A betacoronavirus NS2 proteins and the homologous torovirus Berne pp1a carboxy-terminal domain are phosphodiesterases that antagonize activation of RNase L

Stephen A. Goldstein, Joshua M. Thornbrough, Rong Zhang, Babal K. Jha, Yize Li, Ruth Elliott, Katherine Quiroz-Figueroa, Annie I. Chen, Robert H. Silverman, Susan R. Weiss

Research output: Contribution to journalArticlepeer-review

Abstract

Viruses in the family Coronaviridae, within the order Nidovirales, are etiologic agents of a range of human and animal diseases, including both mild and severe respiratory diseases in humans. These viruses encode conserved replicase and structural proteins as well as more diverse accessory proteins, encoded in the 3' ends of their genomes, that often act as host cell antagonists. We previously showed that 2',5'-phosphodiesterases (2',5'-PDEs) encoded by the prototypical Betacoronavirus, mouse hepatitis virus (MHV), and by Middle East respiratory syndrome-associated coronavirus antagonize the oligoadenylate-RNase L (OAS-RNase L) pathway. Here we report that additional coronavirus superfamily members, including lineage A betacoronaviruses and toroviruses infecting both humans and animals, encode 2',5'-PDEs capable of antagonizing RNase L. We used a chimeric MHV system (MHVMut) in which exogenous PDEs were expressed from an MHV backbone lacking the gene for a functional NS2 protein, the endogenous RNase L antagonist. With this system, we found that 2',5'-PDEs encoded by the human coronavirus HCoV-OC43 (OC43; an agent of the common cold), human enteric coronavirus (HECoV), equine coronavirus (ECoV), and equine torovirus Berne (BEV) are enzymatically active, rescue replication of MHVMut in bone marrow-derived macrophages, and inhibit RNase L-mediated rRNA degradation in these cells. Additionally, PDEs encoded by OC43 and BEV rescue MHVMut replication and restore pathogenesis in wild-type (WT) B6 mice. This finding expands the range of viruses known to encode antagonists of the potent OAS-RNase L antiviral pathway, highlighting its importance in a range of species as well as the selective pressures exerted on viruses to antagonize it.

Original languageEnglish (US)
Article numbere02201-16
JournalJournal of virology
Volume91
Issue number5
DOIs
StatePublished - 2017
Externally publishedYes

Keywords

  • Interferon antagonist
  • Lineage A coronavirus
  • Oligoadenylate synthetase
  • Phosphodiesterase
  • RNase L
  • Torovirus

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

Fingerprint Dive into the research topics of 'Lineage A betacoronavirus NS2 proteins and the homologous torovirus Berne pp1a carboxy-terminal domain are phosphodiesterases that antagonize activation of RNase L'. Together they form a unique fingerprint.

Cite this