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.
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.
Sanada
Takahito
T
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan.
Takaesu
Giichi
G
Mashima
Ryuichi
R
Yoshida
Ryoko
R
Kobayashi
Takashi
T
Yoshimura
Akihiko
A
D000818:Animals; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000737:chemistry / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008070:Lipopolysaccharides / Q000378:metabolism; D008565:Membrane Proteins / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000502:physiology*; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D018116:Vesiculovirus / Q000378:metabolism; D000097905:Roundabout Proteins
D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D050838:Interferon Regulatory Factor-3; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D051197:Toll-Like Receptor 4; C534487:FLN29 protein, mouse; C494232:IRF3 protein, human; C494233:Irf3 protein, mouse; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C507622:TRAFD1 protein, human; C493487:Tlr4 protein, mouse; C452820:RIGI protein, human