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 and Feng Shao
Caspase-2, a highly conserved member of the caspase family, is considered an initiator caspase that triggers apop-tosis in response to some cellular stresses. Previous studies suggest that an intracellular multi-protein complexPIDDosome, induced by genotoxic stress, serves as a platform for caspase-2 activation. Due to caspase-2’s inabilityto process effector caspases, however, the mechanism underlying caspase-2-mediated cell death upon PIDDosomeactivation remains unclear. Here, we conducted an unbiased genome-wide genetic screen and identified that theBcl2 family protein BID is required for PIDDosome-induced, caspase-2-mediated apoptosis. PIDDosome-activatedcaspase-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 nmo-l/L in activating caspase-2-mediated apoptosis. The HUHS015-series of compounds act as efficient agonists thatdirectly target the interdomain linker in caspase-2, representing a new mode of initiator caspase activation. Humanand mouse caspase-2 differ in two crucial residues in the linker, rendering a selectivity of the agonists for humancaspase-2. The caspase-2 agonists are valuable tools to explore the physiological roles of caspase-2-mediated celldeath and a base for developing small-molecule drugs for relevant diseases.