Hsp27 inhibits cytochrome c-mediated caspase activation by sequestering both pro-caspase-3 and cytochrome c.
Mitochondrial cytochrome c release in response to pro-apoptotic signals leads to the formation of a cytochrome c/Apaf-1/procaspase-9 complex (the apoptosome) and resultant activation of caspase-9 and caspase-3. Here we demonstrate that the molecular chaperone, Hsp27, inhibits this cytochrome c-mediated activation of caspase-3. Immunodepeletion of Hsp27 from cytochrome c-activated cytosols resulted in decreased caspase activity. Furthermore, immunoprecipitation of Hsp27 resulted in the coprecipitation of both cytochrome c and procaspase-3. In reciprocal experiments, immunoprecipitation of both procaspase-3 and cytochrome c resulted in coprecipitation of Hsp27, indicating two independent interactions. These results point to Hsp27 mediating its inhibition of procaspase-3 activation through its ability to sequester both cytochrome c and procaspase-3, and thus prevent the correct formation/function of the apoptosome complex.
Concannon
C G
CG
Department of Biochemistry, National University of Ireland, Galway.
Orrenius
S
S
Samali
A
A
D017209:Apoptosis; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D003574:Cytochrome c Group / Q000378:metabolism*; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000201:enzymology; D011233:Precipitin Tests; D011485:Protein Binding; D013696:Temperature
D061945:Caspase Inhibitors; D003574:Cytochrome c Group; D004792:Enzyme Precursors; D006360:Heat-Shock Proteins; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases