2009年6月12日，北京生命科學(xué)研究所王曉東實(shí)驗(yàn)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(bào)道了蛋白激酶RIP3是決定TNF-α誘導(dǎo)的細(xì)胞壞死的關(guān)鍵蛋白,。
細(xì)胞死亡對(duì)于多細(xì)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(xì)胞壞死目前是動(dòng)物體在發(fā)育過(guò)程中最主要的細(xì)胞死亡類(lèi)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(jī)制將為相關(guān)疾病的治療提供新的科學(xué)依據(jù)。
腫瘤壞死因子TNFα是一個(gè)多效性細(xì)胞因子,，參與調(diào)節(jié)炎癥反應(yīng)、細(xì)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(lèi)似物Smac mimetic能誘導(dǎo)TNFα-依賴(lài)性細(xì)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(dāng)細(xì)胞凋亡受到caspase抑制劑zVAD阻止時(shí),，Smac mimetic能誘導(dǎo)一些細(xì)胞發(fā)生依賴(lài)于TNFα 和RIPK1的細(xì)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R(shí)IP3是調(diào)控TNFα-誘導(dǎo)性細(xì)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(hào)刺激時(shí)，一個(gè)包含有RIP3和RIPK1的蛋白復(fù)合體會(huì)被誘導(dǎo)形成,。過(guò)量表達(dá)的RIP3激酶死亡突變體會(huì)與內(nèi)源性RIPK1相結(jié)合從而抑制細(xì)胞壞死途徑,。他們還發(fā)現(xiàn)RIP3只在一些細(xì)胞中選擇性表達(dá)，其表達(dá)跟TNFα-誘導(dǎo)性細(xì)胞壞死密切相關(guān),。而且,，異位表達(dá)RIP3使得對(duì)TNFα-誘導(dǎo)性細(xì)胞壞死有抗性的細(xì)胞轉(zhuǎn)變成敏感型細(xì)胞。此外,，RIP3基因缺陷性小鼠胚胎成纖維細(xì)胞也完全表現(xiàn)出對(duì)TNFα-誘導(dǎo)性細(xì)胞壞死的抗性,。在雨蛙素誘導(dǎo)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(xì)胞的壞死,，從而有力促進(jìn)了急性胰腺炎的恢復(fù),。
該文章的第一作者何蘇丹為北京生命科學(xué)研究所和中國(guó)協(xié)和醫(yī)科大學(xué)聯(lián)合培養(yǎng)的博士生，論文的其他作者還包括美國(guó)德州大學(xué)西南醫(yī)學(xué)中心的汪來(lái)博士以及杜鳳荷博士和北京生命科學(xué)研究所王濤,。北京生命科學(xué)研究所趙麗萍博士領(lǐng)導(dǎo)的轉(zhuǎn)基因動(dòng)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(xiàng)研究由科技部863項(xiàng)目,、北京市政府和美國(guó)國(guó)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.
