14-3-3-zeta participates in TLR3-mediated TICAM-1 signal-platform formation
14-3-3-zeta participates in TLR3-mediated TICAM-1 signal-platform formation
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DOI：
10.1016/j.molimm.2016.03.010
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发表时间：
2016-05-01
影响因子：
3.6
通讯作者：
Seya, Tsukasa
中科院分区：
文献类型：
--
作者：
Funami, Kenji;Matsumoto, Misako;Seya, Tsukasa
模式识别受体(PRRs)对病原体相关分子模式(PAMPs)的识别在先天免疫信号中具有重要作用。Toll样受体(Toll-like Receptor，TLRs)是一类功能齐全的PRRs，在抗病毒和抗肿瘤宿主防御中起着关键作用。含有TIR结构域的适配器分子1(TICAM-1，又称TRIF)是TLR3和TLR4介导的IRF3激活、晚期核因子-kappaB激活和MAPK介导的AP-1激活的适配分子。当TLR3配体被加入到TLR3阳性细胞中时，TICAM-1与TLR3瞬间相互作用，并在胞浆中形成多聚体。然而，TICAM-1多聚体形成的确切机制仍不清楚。在这项研究中，我们确定14-3-3-Zeta是一个在TLR3介导的信号转导中发挥作用的分子。14-3-3-Zeta基因敲除减少了I型干扰素和炎性细胞因子的产生，减少了IRF3的核转位，减少了TLR3-TICAM-1途径对IKB的磷酸化。此外，TICAM-1通过配体刺激的多聚化被14-3-3-Zeta基因敲除所抑制。这些结果提示14-3-3-Zeta参与TLR3-TICAM-1途径，促进TICAM-1的多聚化形成TICAM-1信号体。(C)2016爱思唯尔有限公司。保留所有权利。
Recognition of pathogen-associated molecular patterns (PAMPs) by pattern-recognition receptors (PRRs) is important in innate immune signaling. Toll-like receptors (TLRs) are well-characterized PRRs and are pivotal in antiviral and antitumor host defense. TIR domain-containing adaptor molecule 1 (TICAM-1, also called TRIF) is an adapter molecule in TLR3- and TLR4-mediated IRF3 activation, late-phase NF-kappa B activation and MAPK-mediated AP-1 activation. When a TLR3 ligand is added to TLR3-positive cells, TICAM-1 transiently interacts with TLR3 and forms multimers in the cytosol. However, the precise mechanism of TICAM-1 multimer formation remains unknown. In this study, we identified 14-3-3-zeta as a molecule that functions in TLR3-mediated signaling. Knockdown of 14-3-3-zeta reduced production of type I interferon and inflammatory cytokines, nuclear translocation of IRF3 and phosphorylation of IKB via the TLR3-TICAM-1 pathway. Furthermore, TICAM-1 multimerization by ligand stimulation was prohibited by 14-3-3-zeta knockdown. These results suggest that 14-3-3-zeta is involved in the TLR3-TICAM-1 pathway in promoting multimerization of TICAM-1 for the formation of a TICAM-1 signalosome. (c) 2016 Elsevier Ltd. All rights reserved.