Caspase-2, a highly conserved member of the caspase family, is considered an initiator caspase that triggers apoptosis in response to some cellular stresses. Previous studies suggest that an intracellular multi-protein complex PIDDosome, induced by genotoxic stress, serves as a platform for caspase-2 activation. Due to caspase-2's inability to process effector caspases, however, the mechanism underlying caspase-2-mediated cell death upon PIDDosome activation remains unclear. Here, we conducted an unbiased genome-wide genetic screen and identified that the Bcl2 family protein BID is required for PIDDosome-induced, caspase-2-mediated apoptosis. PIDDosome-activated caspase-2 directly and functionally processes BID to signal the mitochondrial pathway for apoptosis induction. In addition, a designed chemical screen identified a compound, HUHS015, which specifically activates caspase-2-mediated apoptosis. HUHS015-stimulated apoptosis also requires BID but is independent of the PIDDosome. Through extensive structure-activity relationship efforts, we identified a derivative with a potency of ~60 nmol/L in activating caspase-2-mediated apoptosis. The HUHS015-series of compounds act as efficient agonists that directly target the interdomain linker in caspase-2, representing a new mode of initiator caspase activation. Human and mouse caspase-2 differ in two crucial residues in the linker, rendering a selectivity of the agonists for human caspase-2. The caspase-2 agonists are valuable tools to explore the physiological roles of caspase-2-mediated cell death and a base for developing small-molecule drugs for relevant diseases.

中文翻译：

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解剖 caspase-2 介导的细胞死亡：从内在的 PIDDosome 激活到化学调节。


Caspase-2 是 caspase 家族中高度保守的成员，被认为是一种起始 caspase 酶，可在某些细胞应激下触发细胞凋亡。先前的研究表明，由遗传毒性应激诱导的细胞内多蛋白复合物 PIDDosome 是 caspase-2 激活的平台。然而，由于 caspase-2 无法处理效应子 caspase ，因此 paspase-2 介导的 PIDDosome 激活后细胞死亡的机制仍不清楚。在这里，我们进行了无偏倚的全基因组遗传筛选，并确定 Bcl2 家族蛋白 BID 是 PIDDosome 诱导的 caspase-2 介导的细胞凋亡所必需的。PIDDosome 激活的 caspase-2 直接和功能性地加工 BID，以向线粒体途径发出凋亡诱导信号。此外，一项设计的化学筛选确定了一种化合物 HUHS015，它特异性激活 caspase-2 介导的细胞凋亡。HUHS015刺激的细胞凋亡也需要 BID，但独立于 PIDDosome。通过广泛的构效关系努力，我们鉴定了一种在激活 caspase-2 介导的细胞凋亡方面效力为 ~60 nmol/L 的衍生物。HUHS015 系列化合物作为有效的激动剂，直接靶向 caspase-2 中的结构域间接头，代表了一种起始 caspase 激活的新模式。人和小鼠 caspase-2 在接头中的两个关键残基上不同，因此对人 caspase-2 的激动剂具有选择性。caspase-2 激动剂是探索 caspase-2 介导的细胞死亡生理作用的宝贵工具，也是开发相关疾病小分子药物的基础。