Chew Su Kit, Chen Po, Link Nichole, Galindo Kathleen A, Pogue Kristi, Abrams John M
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
Nature. 2009 Jul 2;460(7251):123-7. doi: 10.1038/nature08087. Epub 2009 May 31.
Apoptosis is a conserved form of programmed cell death firmly established in the aetiology, pathogenesis and treatment of many human diseases. Central to the core machinery of apoptosis are the caspases and their proximal regulators. Current models for caspase control involve a balance of opposing elements, with variable contributions from positive and negative regulators among different cell types and species. To advance a comprehensive view of components that support caspase-dependent cell death, we conducted a genome-wide silencing screen in the Drosophila model. Our strategy used a library of double-stranded RNAs together with a chemical antagonist of Inhibitor of apoptosis proteins (IAPs) that simulates the action of native regulators in the Reaper and Smac (also known as Diablo) families. Here we present a highly validated set of targets that is necessary for death provoked by several stimuli. Among these, Tango7 is identified as a new effector. Cells depleted for this gene resisted apoptosis at a step before the induction of effector caspase activity, and the directed silencing of Tango7 in Drosophila prevented caspase-dependent programmed cell death. Unlike known apoptosis regulators in this model system, Tango7 activity did not influence stimulus-dependent loss of Drosophila DIAP1 (also known as th and IAP1), but instead regulated levels of the apical caspase Dronc (Nc). Similarly, the human Tango7 counterpart, PCID1 (also known as EIF3M), impinged on caspase 9, revealing a new regulatory axis affecting the apoptosome.
细胞凋亡是一种保守的程序性细胞死亡形式，在许多人类疾病的病因、发病机制和治疗中已得到明确证实。半胱天冬酶及其近端调节因子是细胞凋亡核心机制的关键。目前关于半胱天冬酶控制的模型涉及相反因素的平衡，不同细胞类型和物种中正负调节因子的贡献各不相同。为了全面了解支持半胱天冬酶依赖性细胞死亡的成分，我们在果蝇模型中进行了全基因组沉默筛选。我们的策略使用了双链RNA文库以及凋亡抑制蛋白（IAP）的化学拮抗剂，该拮抗剂模拟了收割者和Smac（也称为暗黑破坏神）家族中天然调节因子的作用。在此，我们展示了一组经过高度验证的靶点，这些靶点是几种刺激引发细胞死亡所必需的。其中，Tango7被鉴定为一种新的效应因子。该基因缺失的细胞在效应半胱天冬酶活性诱导之前的一个步骤就抵抗细胞凋亡，并且在果蝇中定向沉默Tango7可阻止半胱天冬酶依赖性程序性细胞死亡。与该模型系统中已知的细胞凋亡调节因子不同，Tango7的活性并不影响果蝇DIAP1（也称为th和IAP1）依赖刺激的缺失，而是调节顶端半胱天冬酶Dronc（Nc）的水平。同样，人类Tango7的对应物PCID1（也称为EIF3M）影响半胱天冬酶9，揭示了一条影响凋亡小体的新调节轴。
