Antiviral activity of human OASL protein is mediated by enhancing signaling of the RIG-I RNA sensor

Immunity. 2014 Jun 19;40(6):936-48. doi: 10.1016/j.immuni.2014.05.007. Epub 2014 Jun 12.

Abstract

Virus infection is sensed in the cytoplasm by retinoic acid-inducible gene I (RIG-I, also known as DDX58), which requires RNA and polyubiquitin binding to induce type I interferon (IFN) and activate cellular innate immunity. We show that the human IFN-inducible oligoadenylate synthetases-like (OASL) protein has antiviral activity and mediates RIG-I activation by mimicking polyubiquitin. Loss of OASL expression reduced RIG-I signaling and enhanced virus replication in human cells. Conversely, OASL expression suppressed replication of a number of viruses in a RIG-I-dependent manner and enhanced RIG-I-mediated IFN induction. OASL interacted and colocalized with RIG-I, and through its C-terminal ubiquitin-like domain specifically enhanced RIG-I signaling. Bone-marrow-derived macrophages from mice deficient for Oasl2 showed that among the two mouse orthologs of human OASL, Oasl2 is functionally similar to human OASL. Our findings show a mechanism by which human OASL contributes to host antiviral responses by enhancing RIG-I activation.

Publication types

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

MeSH terms

  • 2',5'-Oligoadenylate Synthetase / genetics
  • 2',5'-Oligoadenylate Synthetase / immunology*
  • Animals
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / immunology*
  • DNA Virus Infections / immunology*
  • HCT116 Cells
  • HEK293 Cells
  • Humans
  • Immunity, Innate
  • Interferon Regulatory Factor-7 / metabolism
  • Interferon Type I / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Polyubiquitin
  • Protein Binding / immunology
  • RNA Interference
  • RNA Virus Infections / immunology*
  • RNA, Small Interfering
  • Signal Transduction / immunology
  • Virus Replication / immunology

Substances

  • IRF7 protein, human
  • Interferon Regulatory Factor-7
  • Interferon Type I
  • RNA, Small Interfering
  • Polyubiquitin
  • OASL protein, human
  • Oasl2 protein, mouse
  • 2',5'-Oligoadenylate Synthetase
  • DDX58 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases