LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA

PLoS One. 2013 May 9;8(5):e64202. doi: 10.1371/journal.pone.0064202. Print 2013.

Abstract

The DExD/H box RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation associated gene-5 (mda-5) sense viral RNA in the cytoplasm of infected cells and activate signal transduction pathways that trigger the production of type I interferons (IFNs). Laboratory of genetics and physiology 2 (LGP2) is thought to influence IFN production by regulating the activity of RIG-I and mda-5, although its mechanism of action is not known and its function is controversial. Here we show that expression of LGP2 potentiates IFN induction by polyinosinic-polycytidylic acid [poly(I:C)], commonly used as a synthetic mimic of viral dsRNA, and that this is particularly significant at limited levels of the inducer. The observed enhancement is mediated through co-operation with mda-5, which depends upon LGP2 for maximal activation in response to poly(I:C). This co-operation is dependent upon dsRNA binding by LGP2, and the presence of helicase domain IV, both of which are required for LGP2 to interact with mda-5. In contrast, although RIG-I can also be activated by poly(I:C), LGP2 does not have the ability to enhance IFN induction by RIG-I, and instead acts as an inhibitor of RIG-I-dependent poly(I:C) signaling. Thus the level of LGP2 expression is a critical factor in determining the cellular sensitivity to induction by dsRNA, and this may be important for rapid activation of the IFN response at early times post-infection when the levels of inducer are low.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / genetics
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • HEK293 Cells
  • Humans
  • Immunoblotting
  • Interferon Type I / genetics
  • Interferon Type I / metabolism
  • Interferon-Induced Helicase, IFIH1
  • Poly I-C / pharmacology
  • Protein Binding
  • RNA Helicases / genetics
  • RNA Helicases / metabolism*
  • RNA Interference
  • RNA, Double-Stranded / genetics
  • RNA, Double-Stranded / metabolism*
  • Receptors, Immunologic
  • Transcriptional Activation / drug effects
  • Two-Hybrid System Techniques
  • Viral Proteins / genetics
  • Viral Proteins / metabolism

Substances

  • Interferon Type I
  • RNA, Double-Stranded
  • Receptors, Immunologic
  • V protein, Paramyxovirus
  • Viral Proteins
  • DHX58 protein, human
  • DDX58 protein, human
  • IFIH1 protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1
  • RNA Helicases
  • Poly I-C