Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 283, Issue 49, Pages 33858-33864Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M806923200
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- National Institute of Biomedical Innovation (NIBIO)
- Nakatomi Foundation
- Takeda Science Foundation
- Kato Memorial Trust Foundation for Nanbyo Research
- Suzuken Memorial Foundation
- Japan Intractable Disease Research Foundation
- Mitsubishi Pharma Research Foundation
- Uehara Memorial Foundation
- Astellas Foundation for Research on Metabolic Disorders
- Yakult Bioscience Research Foundation
- Princess Takamatsu Cancer Research Fund
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FLN29 was identified as an interferon (IFN)-inducible gene, and it has been shown to suppress Toll-like receptor 4-mediated NF-kappa B 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-kappa B 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.
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