FLN29, a novel interferon- and LPS-inducible gene acting as a negative regulator of toll-like receptor signaling
FLN29, a novel interferon- and LPS-inducible gene acting as a negative regulator of toll-like receptor signaling
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DOI：
10.1074/jbc.m508221200
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发表时间：
2005-12-16
影响因子：
4.8
通讯作者：
Yoshimura, A
中科院分区：
文献类型：
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作者：
Mashima, R;Saeki, K;Yoshimura, A
脂多糖(LPS)通过Toll样受体(TLR)4激活巨噬细胞。尽管TLR信号通路的机制已被阐明，但对内毒素，尤其是对内毒素耐受性的负调控机制仍不清楚。在这项研究中，我们发现并鉴定了一个新的干扰素和内毒素诱导基因Fln29，它包含一个与TRAF6相关的锌指基序和与TRAF家族成员相关的NF-kappa B激活物相关序列。Fln29的诱导依赖于STAT1。在巨噬细胞样生成细胞中强制表达Fln29可抑制TLR介导的核因子-kappaB和丝裂原活化蛋白激酶的激活，而小干扰RNA降低Fln29的表达可部分抵消内毒素信号的下调。此外，我们还证实了Fln29的共表达抑制了TRAF6和TAB2诱导的NF-kappa B的激活，提示Fln29可能调节TRAF6的下游。综上所述，Fln29是一种新的TLR信号负反馈调节因子。
Lipopolysaccharide (LPS) activates macrophages through toll-like receptor (TLR) 4. Although the mechanism of the TLR signaling pathway has been well documented, the mechanism of the negative regulation in response to LPS, particularly LPS tolerance, is still poorly understood. In this study we identified and characterized a novel interferon- and LPS-inducible gene, FLN29, which contains a TRAF6-related zinc finger motif and TRAF family member-associated NF-kappa B activator-related sequences. The induction of FLN29 was dependent on STAT1. The forced expression of FLN29 in macrophage-like RAW cells resulted in the suppression of TLR-mediated NF-kappa B and mitogen-activated protein kinase activation, while a reduced expression of FLN29 by small interfering RNA partly cancelled the down-regulation of LPS signaling. Furthermore, we demonstrated that NF-kappa B activation induced by TRAF6 and TAB2 was impaired by co-expression of FLN29, suggesting FLN29 may regulate the downstream of TRAF6. Taken together, FLN29 is a new negative feedback regulator of TLR signaling.