2009年6月12日，北京生命科學研究所王曉東實驗室在Cell上發(fā)表題為“Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-α”的文章,。該文章報道了蛋白激酶RIP3是決定TNF-α誘導的細胞壞死的關(guān)鍵蛋白,。
細胞死亡對于多細胞生物體的發(fā)育和自穩(wěn)平衡起著至關(guān)重要的作用。程序性細胞壞死目前是動物體在發(fā)育過程中最主要的細胞死亡類型之一,，并且參與缺血性心腦血管疾病和神經(jīng)退行性等疾病的發(fā)生,。因此，闡明程序性壞死的分子機制將為相關(guān)疾病的治療提供新的科學依據(jù),。
腫瘤壞死因子TNFα是一個多效性細胞因子,，參與調(diào)節(jié)炎癥反應、細胞凋亡和壞死等,。王曉東課題組以前已經(jīng)發(fā)現(xiàn)Smac/Diablo蛋白的類似物Smac mimetic能誘導TNFα-依賴性細胞凋亡,，此途徑需要激酶RIPK1的參與。有趣的是，該課題組在本研究中發(fā)現(xiàn)當細胞凋亡受到caspase抑制劑zVAD阻止時,，Smac mimetic能誘導一些細胞發(fā)生依賴于TNFα 和RIPK1的細胞壞死,。他們利用高通量RNAi篩選技術(shù)鑒定了RIPK1的同家族蛋白RIP3是調(diào)控TNFα-誘導性細胞壞死的關(guān)鍵蛋白，其激酶活性是必不可少的,。在受到壞死信號刺激時,，一個包含有RIP3和RIPK1的蛋白復合體會被誘導形成。過量表達的RIP3激酶死亡突變體會與內(nèi)源性RIPK1相結(jié)合從而抑制細胞壞死途徑,。他們還發(fā)現(xiàn)RIP3只在一些細胞中選擇性表達,，其表達跟TNFα-誘導性細胞壞死密切相關(guān)。而且,，異位表達RIP3使得對TNFα-誘導性細胞壞死有抗性的細胞轉(zhuǎn)變成敏感型細胞,。此外，RIP3基因缺陷性小鼠胚胎成纖維細胞也完全表現(xiàn)出對TNFα-誘導性細胞壞死的抗性,。在雨蛙素誘導的小鼠急性胰腺炎模型中,，RIP3基因的敲除顯著地減少了胰腺細胞的壞死，從而有力促進了急性胰腺炎的恢復,。
該文章的第一作者何蘇丹為北京生命科學研究所和中國協(xié)和醫(yī)科大學聯(lián)合培養(yǎng)的博士生,，論文的其他作者還包括美國德州大學西南醫(yī)學中心的汪來博士以及杜鳳荷博士和北京生命科學研究所王濤。北京生命科學研究所趙麗萍博士領(lǐng)導的轉(zhuǎn)基因動物中心制備了RIP3基因敲除小鼠,，苗林參與了主要工作,。王曉東博士為本文的通訊作者。該項研究由科技部863項目,、北京市政府和美國國家腫瘤研究所（NCI）資助,。（生物谷Bioon.com）
生物谷推薦原始出處：
Cell, 12 June 2009 doi:10.1016/j.cell.2009.05.021
Receptor Interacting Protein Kinase-3 Determines Cellular Necrotic Response to TNF-α
Sudan He1,2,Lai Wang3,Lin Miao2,Tao Wang2,Fenghe Du3,Liping Zhao2andXiaodong Wang3,,
1 Graduate Program, Peking union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China
2 National Institute of Biological Sciences, No. 7 Science Park Road, Zhongguancun Life Science Park, Beijing 102206, China
3 Howard Hughes Medical Institute, Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
Smac mimetics induce apoptosis synergistically with TNF- 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- family of death-inducing cytokines.
