FLN29 deficiency reveals its negative regulatory role in the Toll-like receptor (TLR) and retinoic acid-inducible gene I (RIG-I)-like helicase signaling pathway

J Biol Chem. 2008 Dec 5;283(49):33858-64. doi: 10.1074/jbc.M806923200. Epub 2008 Oct 10.

Abstract

FLN29 was identified as an interferon (IFN)-inducible gene, and it has been shown to suppress Toll-like receptor 4-mediated NF-kappaB activation by binding to TRAF6. To elucidate the physiological roles of FLN29, we generated FLN29-deficient mice. FLN29 deficiency resulted in hyper-response to LPS both in vivo and in vitro, demonstrating the negative regulatory role of FLN29 in TLR4 signaling. Furthermore, we found that FLN29(-/-) mice exhibited increased susceptibility to poly(I:C)-induced septic shock compared with WT mice. FLN29(-/-) fibroblasts were highly resistant to vesicular stomatitis virus infection, and these cells produced more IFN-beta than WT cells did in response to not only intracellular poly(I:C) but also overexpression of IPS-1. Forced expression of FLN29 inhibited the IPS-1-dependent activation of both NF-kappaB and IRF3. We also found that FLN29 could interact with TRIF, IPS-1, TRAF3, and TRAF6. Together, these results suggest that FLN29, in addition to playing a negative regulatory role in the TLR4 signaling pathway, negatively regulates the RIG-I-like helicase signaling pathway at the level of IPS-1/TRAF6 and IPS-1/TRAF3 complexes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / chemistry
  • DEAD-box RNA Helicases / physiology*
  • Gene Expression Regulation*
  • Humans
  • Interferon Regulatory Factor-3 / metabolism
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology*
  • Lipopolysaccharides / metabolism
  • Membrane Proteins / chemistry
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Transgenic
  • NF-kappa B / metabolism
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / physiology*
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Signal Transduction
  • Toll-Like Receptor 4 / metabolism
  • Vesiculovirus / metabolism

Substances

  • FLN29 protein, mouse
  • IRF3 protein, human
  • Interferon Regulatory Factor-3
  • Intracellular Signaling Peptides and Proteins
  • Irf3 protein, mouse
  • Lipopolysaccharides
  • Membrane Proteins
  • NF-kappa B
  • Nerve Tissue Proteins
  • Receptors, Cell Surface
  • Receptors, Immunologic
  • Robo3 protein, mouse
  • TRAFD1 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4
  • RIGI protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases