Caspase-2 can function upstream of bid cleavage in the TRAIL apoptosis pathway.
In many mammalian cell types, engagement of the TRAIL/Apo2L death receptors DR4 and DR5 alters mitochondrial physiology, thereby promoting the release of pro-apoptotic proteins normally contained within this organelle. A contemporary view of this process is that in so-called type II cells death receptor-activated caspase-8 cleaves the Bcl-2 family member Bid, which generates a truncated Bid fragment that collaborates with Bax, another Bcl-2 relative, to promote the release of mitochondrial factors necessary for activation of executioner caspases and apoptosis. Here we show that in some type II cells caspase-2 is necessary for optimal TRAIL-mediated cleavage of Bid. Down-regulation of caspase-2 using RNA interference significantly inhibited TRAIL-induced apoptosis. Analysis of the TRAIL proteolytic cascade following gene silencing of specific pathway components revealed that caspase-2 is necessary for efficient cleavage of Bid; however, caspase-2 proteolytic processing, which occurs downstream of Bax, is not necessary for its role in Bid cleavage.
Wagner
Klaus W
KW
Department of Cancer Biology, Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, CA 92121, USA.
Engels
Ingo H
IH
Deveraux
Quinn L
QL
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins; D051023:BH3 Interacting Domain Death Agonist Protein; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D053143:Caspase 2; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D020169:Caspases / Q000378:metabolism / Q000502:physiology*; D016923:Cell Death; D002460:Cell Line; D002470:Cell Survival; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004789:Enzyme Activation; D005047:Etoposide / Q000494:pharmacology; D020868:Gene Silencing; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism; D008954:Models, Biological; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D013778:Tetrazolium Salts; D013844:Thiazoles; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D005047:Etoposide; C505407:CASP3 protein, human; C505520:CASP7 protein, human; C505530:CASP8 protein, human; D053143:Caspase 2; D053148:Caspase 3; D053179:Caspase 7; D053181:Caspase 8; D020169:Caspases; C022616:thiazolyl blue; D019311:Staurosporine