TLR3/TICAM-1 signaling in tumor cell RIP3-dependent necroptosis.
TLR3/TICAM-1 signaling in tumor cell RIP3-dependent necroptosis.
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DOI：
10.4161/onci.21244
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发表时间：
2012-09-01
期刊：
影响因子：
7.2
通讯作者：
Matsumoto M
中科院分区：
文献类型：
--
作者：
Seya T;Shime H;Takaki H;Azuma M;Oshiumi H;Matsumoto M
Toll样受体3（TLR 3）的参与导致衔接子TICAM-1（TRIF）的寡聚化，其可以诱导三种急性细胞应答中的任一种，即与I型干扰素产生偶联的细胞存活，或通过凋亡或坏死的细胞死亡。由TLR 3引起的特异性反应决定了受影响细胞的命运，尽管在TLR 3刺激的细胞中两种细胞死亡途径之间的转换机制在分子上仍然未知。肿瘤坏死因子α（TNFα）介导的细胞死亡可通过细胞凋亡或非细胞凋亡途径进行，称为坏死性凋亡或程序性坏死，已对其进行了详细描述。有趣的是，包含死亡结构域的激酶称为受体相互作用蛋白激酶（RIP）参与导致这两种细胞死亡途径的信号传导途径。在不存在半胱天冬酶8活性的情况下，RIP 1/RIP 3复合物（称为坏死体）的形成对于响应TNFα信号传导诱导坏死性凋亡至关重要。另一方面，已知RIP 1与TICAM-1的C-末端结构域相互作用并调节TLR 3信号传导。在巨噬细胞和可能的肿瘤细胞系中，RIP 1/RIP 3介导的坏死性细胞死亡可导致TLR激动剂polyI：C的施用。如果这涉及TLR 3/TICAM-1通路，则病毒dsRNA的先天传感将与细胞病变效应和持续性炎症相关，从而有利于微环境中损伤相关分子模式（DAMP）的释放。在这里，我们回顾了越来越多的证据，指出TLR 3/TICAM-1轴参与肿瘤细胞坏死性凋亡和随后释放DAMPs。
The engagement of Toll-like receptor 3 (TLR3) leads to the oligomerization of the adaptor TICAM-1 (TRIF), which can induces either of three acute cellular responses, namely, cell survival coupled to Type I interferon production, or cell death, via apoptosis or necrosis. The specific response elicited by TLR3 determines the fate of affected cells, although the switching mechanism between the two cell death pathways in TLR3-stimulated cells remains molecularly unknown. Tumor necrosis factor α (TNFα)-mediated cell death can proceed via apoptosis or via a non-apoptotic pathway, termed necroptosis or programmed necrosis, which have been described in detail. Interestingly, death domain-containing kinases called receptor-interacting protein kinases (RIPs) are involved in the signaling pathways leading to these two cell death pathways. Formation of the RIP1/RIP3 complex (called necrosome) in the absence of caspase 8 activity is crucial for the induction of necroptosis in response to TNFα signaling. On the other hand, RIP1 is known to interact with the C-terminal domain of TICAM-1 and to modulate TLR3 signaling. In macrophages and perhaps tumor cell lines, RIP1/RIP3-mediated necroptotic cell death can ensue the administration of the TLR agonist polyI:C. If this involved the TLR3/TICAM-1 pathway, the innate sensing of viral dsRNA would be linked to cytopathic effects and to persistent inflammation, in turn favoring the release of damage-associated molecular patterns (DAMPs) in the microenvironment. Here, we review accumulating evidence pointing to the involvement of the TLR3/TICAM-1 axis in tumor cell necroptosis and the subsequent release of DAMPs.