Caspase-8 cleaves histone deacetylase 7 and abolishes its transcription repressor function.
Caspase-8 is the initiator caspase of the extrinsic apoptosis pathway and also has a role in non-apoptotic physiologies. Identifying endogenous substrates for caspase-8 by using integrated bioinformatics and biological approaches is required to delineate the diverse roles of this caspase. We describe a number of novel putative caspase-8 substrates using the Prediction of Protease Specificity (PoPS) program, one of which is histone deacetylase 7 (HDAC7). HDAC7 is cleaved faster than any other caspase-8 substrate described to date. It is also cleaved in primary CD4+CD8+ thymocytes undergoing extrinsic apoptosis. By using naturally occurring caspase inhibitors that have evolved exquisite specificity at concentrations found within the cell, we could unequivocally assign the cleavage activity to caspase-8. Importantly, cleavage of HDAC7 alters its subcellular localization and abrogates its Nur77 repressor function. Thus we demonstrate a direct role for initiator caspase-mediated proteolysis in promoting gene transcription.
Scott
Fiona L
FL
Program in Apoptosis and Cell Death Research, Burnham Institute for Medical Research, La Jolla, California 92037, USA. fscott@burnham.org
Fuchs
Greg J
GJ
Boyd
Sarah E
SE
Denault
Jean-Bernard
JB
Hawkins
Christine J
CJ
Dequiedt
Franck
F
Salvesen
Guy S
GS
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D019556:COS Cells; D053181:Caspase 8 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011480:Protease Inhibitors / Q000737:chemistry / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012984:Software; D013379:Substrate Specificity / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology*
D061945:Caspase Inhibitors; D004268:DNA-Binding Proteins; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011480:Protease Inhibitors; D011987:Receptors, Steroid; D012097:Repressor Proteins; D053181:Caspase 8; C543273:HDAC7 protein, human; C543274:Hdac7 protein, mouse; D006655:Histone Deacetylases