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 Deficiency Reveals Its Negative Regulatory Role in the Toll-like Receptor (TLR) and Retinoic Acid-inducible Gene I (RIG-I)-like Helicase Signaling Pathway
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DOI：
10.1074/jbc.m806923200
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发表时间：
2008-12-05
影响因子：
4.8
通讯作者：
Yoshimura, Akihiko
中科院分区：
文献类型：
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作者：
Sanada, Takahito;Takaesu, Giichi;Yoshimura, Akihiko
FLN 29被鉴定为干扰素（IFN）诱导型基因，并且已显示其通过与TRAF 6结合来抑制Toll样受体4介导的NF-κ B活化。为了阐明FLN 29的生理作用，我们产生了FLN 29缺陷型小鼠。FLN 29缺陷导致体内和体外对LPS的超应答，证明了FLN 29在TLR 4信号传导中的负调节作用。此外，我们发现与WT小鼠相比，FLN 29（-/-）小鼠表现出对poly（I：C）诱导的脓毒性休克的易感性增加。FLN 29（-/-）成纤维细胞对水疱性口炎病毒感染具有高度抗性，并且这些细胞不仅响应于细胞内poly（I：C）而且响应于IPS-1的过表达而产生比WT细胞更多的IFN-β。FLN 29的强制表达抑制了NF-κ B和IRF 3的IPS-1依赖性活化。我们还发现FLN 29可以与TRIF、IPS-1、TRAF 3和TRAF 6相互作用。总之，这些结果表明，FLN 29除了在TLR 4信号通路中发挥负调节作用外，还在IPS-1/TRAF 6和IPS-1/TRAF 3复合物水平负调节RIG-I样解旋酶信号通路。
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.