title: Heat shock induces apoptosis independently of any known initiator caspase-activating complex.
abstract: Adaptive responses to mild heat shock are among the most widely conserved and studied in nature. More intense heat shock, however, induces apoptosis through mechanisms that remain largely unknown. Herein, we present evidence that heat shock activates an apical protease that stimulates mitochondrial outer membrane permeabilization and processing of the effector caspase-3 in a benzyloxycarbonyl-VAD-fluoromethyl ketone (polycaspase inhibitor)- and Bcl-2-inhibitable manner. Surprisingly, however, neither FADD.caspase-8 nor RAIDD.caspase-2 PIDDosome (p53-induced protein with a death domain) complexes were detected in dying cells, and neither of these initiator caspases nor the endoplasmic reticulum stress-activated caspases-4/12 were required for mitochondrial outer membrane permeabilization. Similarly, although cytochrome c was released from mitochondria following heat shock, functional Apaf-1.caspase-9 apoptosome complexes were not formed, and caspase-9 was not essential for the activation of caspase-3 or the induction of apoptosis. Thus, heat shock does not require any of the known initiator caspases or their activating complexes to promote apoptotic cell death but instead relies upon the activation of an apparently novel apical protease with caspase-like activity.
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712; Center for Research on Environmental Disease, The University of Texas at Austin, Austin, Texas 78712.
authors.forename: Rania S
authors.initials: RS
authors.lastname: Milleron
authors.affiliation: Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712; Center for Research on Environmental Disease, The University of Texas at Austin, Austin, Texas 78712; Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas 78712. Electronic address: sbbratton@mail.utexas.edu.
authors.forename: Shawn B
authors.initials: SB
authors.lastname: Bratton
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry; D017209:Apoptosis; D053477:Apoptotic Protease-Activating Factor 1; D053420:CRADD Signaling Adaptor Protein; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D053200:Fas-Associated Death Domain Protein; D006358:Hot Temperature; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008954:Models, Biological; D011506:Proteins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C506592:APAF1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D053477:Apoptotic Protease-Activating Factor 1; D053420:CRADD Signaling Adaptor Protein; C104252:CRADD protein, human; C505533:FADD protein, human; D053200:Fas-Associated Death Domain Protein; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D016159:Tumor Suppressor Protein p53; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases