Dissecting caspase-2-mediated cell death: from intrinsic PIDDosome activation to chemical modulation.

IF 13.6 1区 生物学 Q1 CELL BIOLOGY
Mengxue Zeng, Kun Wang, Qingcui Wu, Jingjin Ding, Dan Xie, Xiangbing Qi, Feng Shao
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引用次数: 0

Abstract

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. However, due to caspase-2's inability to process effector caspases, 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. Additionally, a designed chemical screen identified a compound, HUHS015, that 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.

剖析caspase-2介导的细胞死亡:从内在PIDDosome激活到化学调制。
Caspase-2是caspase家族中一个高度保守的成员,被认为是一种启动caspase,可在某些细胞应激反应中触发细胞凋亡。以前的研究表明,由基因毒性应激诱导的细胞内多蛋白复合物 PIDDosome 是激活 Caspase-2 的平台。然而,由于caspase-2不能处理效应caspases,PIDDosome激活后caspase-2介导细胞死亡的机制仍不清楚。在这里,我们进行了一次无偏见的全基因组遗传筛选,发现Bcl2家族蛋白BID是PIDDosome诱导、caspase-2介导的细胞凋亡所必需的。PIDDosome激活的caspase-2直接对BID进行功能处理,为线粒体诱导凋亡途径发出信号。此外,通过设计化学筛选发现了一种能特异性激活 caspase-2 介导的细胞凋亡的化合物 HUHS015。HUHS015 刺激的细胞凋亡也需要 BID,但与 PIDDosome 无关。通过广泛的结构-活性关系研究,我们发现了一种衍生物,其激活 caspase-2 介导的细胞凋亡的效力约为 60 nmol/L。HUHS015 系列化合物是直接针对 caspase-2 中域间连接器的高效激动剂,代表了一种新的启动器 caspase 激活模式。人类和小鼠的 caspase-2 在连接体的两个关键残基上存在差异,因此这些激动剂对人类 caspase-2 具有选择性。caspase-2 激动剂是探索 caspase-2 介导的细胞死亡的生理作用的宝贵工具,也是开发治疗相关疾病的小分子药物的基础。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Protein & Cell
Protein & Cell CELL BIOLOGY-
CiteScore
24.00
自引率
0.90%
发文量
1029
审稿时长
6-12 weeks
期刊介绍: Protein & Cell is a monthly, peer-reviewed, open-access journal focusing on multidisciplinary aspects of biology and biomedicine, with a primary emphasis on protein and cell research. It publishes original research articles, reviews, and commentaries across various fields including biochemistry, biophysics, cell biology, genetics, immunology, microbiology, molecular biology, neuroscience, oncology, protein science, structural biology, and translational medicine. The journal also features content on research policies, funding trends in China, and serves as a platform for academic exchange among life science researchers.
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