Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-α
Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-α
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DOI：
10.1016/j.cell.2009.05.021
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发表时间：
2009-06-12
期刊：
影响因子：
64.5
通讯作者：
Wang, Xiaodong
中科院分区：
文献类型：
--
作者：
He, Sudan;Wang, Lai;Wang, Xiaodong
Smac模拟物通过触发含有受体相互作用蛋白激酶-1（RIPK 1）的半胱天冬酶-8激活复合物的形成与TNF-α协同诱导细胞凋亡。半胱天冬酶抑制剂在许多类型的细胞中阻断这种形式的细胞凋亡。然而，在其他几种细胞系中，半胱天冬酶抑制剂将凋亡反应转变为坏死。全基因组siRNA筛选揭示了RIP激酶家族的另一个成员RIP 3是坏死所需的。RIP 3在不同细胞系中的表达与它们对坏死诱导的反应性相关。RIP 3的激酶活性对于坏死执行是必不可少的。在诱导坏死后，RIP 3被募集至RIPK 1以形成坏死诱导复合物。在急性胰腺炎模型中，来自RIP 3敲除小鼠的胚胎成纤维细胞对坏死具有抗性，并且RIP 3敲除动物没有炎症引起的组织损伤。这些数据表明RIP 3是响应于死亡诱导细胞因子的TNF-α家族的细胞坏死的决定因素。
Smac mimetics induce apoptosis synergistically with TNF-alpha by triggering the formation of a caspase-8-activating complex containing receptor interacting protein kinase-1 (RIPK1). Caspase inhibitors block this form of apoptosis in many types of cells. However, in several other cell lines, caspase inhibitors switch the apoptotic response to necrosis. A genome wide siRNA screen revealed another member of the RIP kinase family, RIP3, to be required for necrosis. The expression of RIP3 in different cell lines correlates with their responsiveness to necrosis induction. The kinase activity of RIP3 is essential for necrosis execution. Upon induction of necrosis, RIP3 is recruited to RIPK1 to form a necrosis-inducing complex. Embryonic fibroblasts from RIP3 knockout mice are resistant to necrosis and RIP3 knockout animals are devoid of inflammation inflicted tissue damage in an acute pancreatitis model. These data indicate RIP3 as the determinant for cellular necrosis in response to TNF-alpha family of death-inducing cytokines.