1月20日，Cell杂志上刊登了王晓东研究组同期发表的两篇文章，阐述有关TNF-α诱导的细胞坏死信号传导通路中新的发现。
与人们早期的认识不同，现在细胞坏死被认为是哺乳动物的发育和生理过程的重要组成部分。此外，细胞坏死还参与了人类的多种病理过程，如急性组织损伤以及许多免疫性疾病。许多研究结果显示细胞坏死是由复杂的分子信号通路所执行的。除RIP1以外，王晓东实验室之前的研究证实了RIP3的激酶活性是肿瘤坏死因子TNF-α诱导的细胞坏死过程中不可或缺的。当细胞坏死被诱导之后，RIP1、RIP3相互结合形成一个信号复合体，被称作“necrosome”。这一特殊的信号复合体怎样把坏死的信号传递下去并不清楚。
在这一期的Cell中，王晓东研究组同期发表了两篇文章阐述有关TNF-α诱导的细胞坏死信号传导通路中新的发现。他们发现一个名叫MLKL的蛋白在细胞坏死中起着关键性作用。这是有关这一蛋白研究的第一篇文章。研究表明在RIP3介导的细胞坏死信号通路中，MLKL扮演着RIP3激酶其中一个底物的角色。与此同时，他们还筛选得到一个抑制细胞坏死的小分子化合物，通过特异识别MLKL阻止坏死信号的传导。另外，MLKL将“necrosome”与线粒体磷酸酶PGAM5相联系起来。PGAM5的激活可以导致成串排列的线粒体发生线性断裂，这一现象在细胞坏死发生的早期起到了非常重要的作用。更有趣的是，PGAM5在多种原因造成的细胞坏死通路中占据枢纽的作用，参与例如氧自由基的过量增长和钙离子的过度渗漏等引起的细胞坏死。他们的工作呈现给我们有关细胞坏死更加详细的分子机制，并将细胞坏死与线粒体的故障联系了起来。这对于我们设计并开发针对细胞坏死相关疾病的药物起到了极大的提示和推动作用。
文章的主要工作由孙丽明博士、汪志高博士和王华翌博士完成。何苏丹博士、汪来博士、蒋辉博士、杜凤荷博士和晏家骢参与了课题的相关部分。化学部分的工作由合作者雷晓光实验室的廖道红和刘伟龙完成。蛋白质组中心的陈涉提供了质谱分析。
在达拉斯的研究工作由霍华德休斯医学研究所和美国国家肿瘤研究所（NCI）(PO1 CA95471)资助。在北京的研究工作由科技部863(2008AA022318)和973(2010CB835400)项目和北京市科委资助。(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
