ATP-dependent effector-like functions of RIG-I-like receptors

Mol Cell. 2015 May 7;58(3):541-548. doi: 10.1016/j.molcel.2015.03.014. Epub 2015 Apr 16.

Abstract

The vertebrate antiviral innate immune system is often considered to consist of two distinct groups of proteins: pattern recognition receptors (PRRs) that detect viral infection and induce the interferon (IFN) signaling, and effectors that directly act against viral replication. Accordingly, previous studies on PRRs, such as RIG-I and MDA5, have primarily focused on their functions in viral double-stranded RNA (dsRNA) detection and consequent antiviral signaling. We report here that both RIG-I and MDA5 efficiently displace viral proteins pre-bound to dsRNA in a manner dependent on their ATP hydrolysis, and that this activity assists a dsRNA-dependent antiviral effector protein, PKR, and allows RIG-I to promote MDA5 signaling. Furthermore, truncated RIG-I/MDA5 lacking the signaling domain, and hence the IFN stimulatory activity, displaces viral proteins and suppresses replication of certain viruses in an ATP-dependent manner. Thus, this study reveals novel "effector-like" functions of RIG-I and MDA5 that challenge the conventional view of PRRs.

Publication types

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

MeSH terms

  • Adenosine Triphosphate / metabolism*
  • Antiviral Agents / metabolism
  • Base Sequence
  • Blotting, Western
  • Cell Line, Tumor
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • HEK293 Cells
  • Humans
  • Interferon-Induced Helicase, IFIH1
  • Interferon-beta / genetics
  • Interferon-beta / metabolism
  • Models, Molecular
  • Mutation
  • Nucleic Acid Conformation
  • Phosphorylation
  • RNA Interference
  • RNA, Double-Stranded / chemistry
  • RNA, Double-Stranded / genetics
  • RNA, Double-Stranded / metabolism
  • RNA, Viral / chemistry
  • RNA, Viral / genetics
  • RNA, Viral / metabolism
  • Receptors, Pattern Recognition / genetics
  • Receptors, Pattern Recognition / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Viral Proteins / genetics
  • Viral Proteins / metabolism
  • Virus Diseases / genetics
  • Virus Diseases / metabolism
  • eIF-2 Kinase / genetics
  • eIF-2 Kinase / metabolism

Substances

  • Antiviral Agents
  • RNA, Double-Stranded
  • RNA, Viral
  • Receptors, Pattern Recognition
  • Viral Proteins
  • Interferon-beta
  • Adenosine Triphosphate
  • eIF-2 Kinase
  • DDX58 protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1