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

Mengxue ZENG; Kun WANG; Qingcui WU; Jingjin DING; Dan XIE; Xiangbing QI; Feng SHAO

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

Author: Mengxue ZENG ¹ ; Kun WANG ² ; Qingcui WU ² ; Jingjin DING ² ; Dan XIE ¹ ; Xiangbing QI ² ; Feng SHAO ¹
Author Information

1. State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
2. National Institute of Biological Sciences, Beijing, Beijing 102206, China.
Publication Type:Journal Article
Keywords: BID; PIDDosome; agonist; apoptosis; caspase-2; chemical screen
MeSH: Caspase 2/genetics*; Humans; BH3 Interacting Domain Death Agonist Protein/metabolism*; Apoptosis/drug effects*; Death Domain Receptor Signaling Adaptor Proteins/metabolism*; Animals; Mice; Cysteine Endopeptidases
From: Protein & Cell 2024;15(12):889-905
CountryChina
Language:English
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. 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.