Toll-like Receptor 3-mediated Necrosis via TRIF, RIP3, and MLKL
Toll-like Receptor 3-mediated Necrosis via TRIF, RIP3, and MLKL
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DOI：
10.1074/jbc.m113.462341
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发表时间：
2013-10-25
影响因子：
4.8
通讯作者：
Mocarski, Edward S.
中科院分区：
文献类型：
--
作者：
Kaiser, William J.;Sridharan, Haripriya;Mocarski, Edward S.
Toll样受体（TLR）信号传导由病原体相关分子模式触发，所述病原体相关分子模式介导已建立的丝氨酸驱动的途径，激活NF-κ B以及IRF 3/IRF 7。此外，TLR 3驱动半胱天冬酶8调节的程序性细胞死亡途径，使人联想到TNF家族死亡受体信号传导。我们发现，在TLR 2、TLR 3、TLR 4、TLR 5或TLR 9的刺激过程中抑制或消除胱天蛋白酶8导致受体相互作用蛋白（RIP）3激酶依赖性程序性坏死，其通过含有TIR结构域的衔接子诱导干扰素-γ（TRIF）或MyD 88信号转导发生。TLR 3或TLR 4通过TRIF与RIP 3激酶（也称为RIPK 3）的RIP同型相互作用基序依赖性缔合直接激活程序性坏死。在成纤维细胞中，该途径独立于RIP 1或其激酶活性进行，但它仍然依赖于RIP 3激酶下游的混合谱系激酶结构域样蛋白（MLKL）。在这里，我们描述了两个小分子RIP 3激酶抑制剂，并利用它们来证明RIP 3激酶在RIP 1-RIP 3，DAI-RIP 3和TRIF-RIP 3复合物诱导的程序性坏死中的共同需求。TLR信号传导后的细胞命运决定与死亡受体信号传导平行，并依赖于半胱天冬酶8来抑制RIP 3依赖性程序性坏死，无论是直接由TRIF-RIP 3-MLKL途径启动还是间接通过TNF活化和RIP 1-RIP 3-MLKL坏死性凋亡途径启动。
Toll-like receptor (TLR) signaling is triggered by pathogen-associated molecular patterns that mediate well established cytokine-driven pathways, activating NF-kappa B together with IRF3/IRF7. In addition, TLR3 drives caspase 8-regulated programmed cell death pathways reminiscent of TNF family death receptor signaling. We find that inhibition or elimination of caspase 8 during stimulation of TLR2, TLR3, TLR4, TLR5, or TLR9 results in receptor interacting protein (RIP) 3 kinase-dependent programmed necrosis that occurs through either TIR domain-containing adapter-inducing interferon-gamma (TRIF) or MyD88 signal transduction. TLR3 or TLR4 directly activates programmed necrosis through a RIP homotypic interaction motif-dependent association of TRIF with RIP3 kinase (also called RIPK3). In fibroblasts, this pathway proceeds independent of RIP1 or its kinase activity, but it remains dependent on mixed lineage kinase domain-like protein (MLKL) downstream of RIP3 kinase. Here, we describe two small molecule RIP3 kinase inhibitors and employ them to demonstrate the common requirement for RIP3 kinase in programmed necrosis induced by RIP1-RIP3, DAI-RIP3, and TRIF-RIP3 complexes. Cell fate decisions following TLR signaling parallel death receptor signaling and rely on caspase 8 to suppress RIP3-dependent programmed necrosis whether initiated directly by a TRIF-RIP3-MLKL pathway or indirectly via TNF activation and the RIP1-RIP3-MLKL necroptosis pathway.