1月20日,,Cell雜志上刊登了王曉東研究組同期發(fā)表的兩篇文章,,闡述有關(guān)TNF-α誘導(dǎo)的細(xì)胞壞死信號傳導(dǎo)通路中新的發(fā)現(xiàn),。
與人們早期的認(rèn)識不同,,現(xiàn)在細(xì)胞壞死被認(rèn)為是哺乳動物的發(fā)育和生理過程的重要組成部分,。此外,,細(xì)胞壞死還參與了人類的多種病理過程,如急性組織損傷以及許多免疫性疾病,。許多研究結(jié)果顯示細(xì)胞壞死是由復(fù)雜的分子信號通路所執(zhí)行的,。除RIP1以外,王曉東實驗室之前的研究證實了RIP3的激酶活性是腫瘤壞死因子TNF-α誘導(dǎo)的細(xì)胞壞死過程中不可或缺的,。當(dāng)細(xì)胞壞死被誘導(dǎo)之后,,RIP1、RIP3相互結(jié)合形成一個信號復(fù)合體,,被稱作“necrosome”,。這一特殊的信號復(fù)合體怎樣把壞死的信號傳遞下去并不清楚。
在這一期的Cell中,,王曉東研究組同期發(fā)表了兩篇文章闡述有關(guān)TNF-α誘導(dǎo)的細(xì)胞壞死信號傳導(dǎo)通路中新的發(fā)現(xiàn),。他們發(fā)現(xiàn)一個名叫MLKL的蛋白在細(xì)胞壞死中起著關(guān)鍵性作用。這是有關(guān)這一蛋白研究的第一篇文章,。研究表明在RIP3介導(dǎo)的細(xì)胞壞死信號通路中,,MLKL扮演著RIP3激酶其中一個底物的角色。與此同時,,他們還篩選得到一個抑制細(xì)胞壞死的小分子化合物,,通過特異識別MLKL阻止壞死信號的傳導(dǎo),。另外,MLKL將“necrosome”與線粒體磷酸酶PGAM5相聯(lián)系起來,。PGAM5的激活可以導(dǎo)致成串排列的線粒體發(fā)生線性斷裂,,這一現(xiàn)象在細(xì)胞壞死發(fā)生的早期起到了非常重要的作用。更有趣的是,,PGAM5在多種原因造成的細(xì)胞壞死通路中占據(jù)樞紐的作用,,參與例如氧自由基的過量增長和鈣離子的過度滲漏等引起的細(xì)胞壞死。他們的工作呈現(xiàn)給我們有關(guān)細(xì)胞壞死更加詳細(xì)的分子機(jī)制,,并將細(xì)胞壞死與線粒體的故障聯(lián)系了起來,。這對于我們設(shè)計并開發(fā)針對細(xì)胞壞死相關(guān)疾病的藥物起到了極大的提示和推動作用。
文章的主要工作由孫麗明博士,、汪志高博士和王華翌博士完成,。何蘇丹博士、汪來博士,、蔣輝博士、杜鳳荷博士和晏家驄參與了課題的相關(guān)部分,?;瘜W(xué)部分的工作由合作者雷曉光實驗室的廖道紅和劉偉龍完成。蛋白質(zhì)組中心的陳涉提供了質(zhì)譜分析,。
在達(dá)拉斯的研究工作由霍華德休斯醫(yī)學(xué)研究所和美國國家腫瘤研究所(NCI)(PO1 CA95471)資助,。在北京的研究工作由科技部863(2008AA022318)和973(2010CB835400)項目和北京市科委資助。(生物谷 Bioon.com)
doi:10.1016/j.cell.2011.11.031
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Mixed Lineage Kinase Domain-like Protein Mediates Necrosis Signaling Downstream of RIP3 Kinase
Liming Sun ,Huayi Wang,Zhigao Wang,Sudan He,She Chen,Daohong Liao ,Lai Wang,Jiacong Yan,Weilong Liu, ,Xiaoguang Lei ,Xiaodong Wang
The receptor-interacting serine-threonine kinase 3 (RIP3) is a key signaling molecule in the programmed necrosis (necroptosis) pathway. This pathway plays important roles in a variety of physiological and pathological conditions, including development, tissue damage response, and antiviral immunity. Here, we report the identification of a small molecule called (E)-N-(4-(N-(3-methoxypyrazin-2-yl)sulfamoyl)phenyl)-3-(5-nitrothiophene-2-yl)acrylamide—hereafter referred to as necrosulfonamide—that specifically blocks necrosis downstream of RIP3 activation. An affinity probe derived from necrosulfonamide and coimmunoprecipitation using anti-RIP3 antibodies both identified the mixed lineage kinase domain-like protein (MLKL) as the interacting target. MLKL was phosphorylated by RIP3 at the threonine 357 and serine 358 residues, and these phosphorylation events were critical for necrosis. Treating cells with necrosulfonamide or knocking down MLKL expression arrested necrosis at a specific step at which RIP3 formed discrete punctae in cells. These findings implicate MLKL as a key mediator of necrosis signaling downstream of the kinase RIP3.
doi:10.1016/j.cell.2011.11.030
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The Mitochondrial Phosphatase PGAM5 Functions at the Convergence Point of Multiple Necrotic Death Pathways
Zhigao Wang,Hui Jiang,She Chen,Fenghe Du,Xiaodong Wang
The programmed necrosis induced by TNF-α requires the activities of the receptor-interacting serine-threonine kinases RIP1 and RIP3 and their interaction with the mixed lineage kinase domain-like protein MLKL. We report the identification of RIP1- and RIP3-containing protein complexes that form specifically in response to necrosis induction. One component of these complexes is the mitochondrial protein phosphatase PGAM5, which presents as two splice variants, PGAM5L (long form) and PGAM5S (short form). Knockdown of either form attenuated necrosis induced by TNF-α as well as reactive oxygen species (ROS) and calcium ionophore, whereas knockdown of RIP3 and MLKL blocked only TNF-α-mediated necrosis. Upon necrosis induction, PGAM5S recruited the mitochondrial fission factor Drp1 and activated its GTPase activity by dephosphorylating the serine 637 site of Drp1. Drp1 activation caused mitochondrial fragmentation, an early and obligatory step for necrosis execution. These data defined PGAM5 as the convergent point for multiple necrosis pathways