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 c...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 caspase2-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.展开更多
基金supported by the National Key R&D Program of China(2022YFA1304700)the CAS Strategic Priority Research Program(XDB37030202)+2 种基金the Basic Science Center Project(82388201)of NSFCthe Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences(2019-I2M-5-084)F.S.is also supported by the Tencent New Cornerstone Investigator Program.
文摘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 caspase2-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.
