Caspase-12 and caspase-4 are not required for caspase-dependent endoplasmic reticulum stress-induced apoptosis.
Alterations in cellular homeostasis that affect protein folding in the endoplasmic reticulum (ER) trigger a signaling pathway known as the unfolded protein response (UPR). The initially cytoprotective UPR will trigger an apoptotic cascade if the cellular insult is not corrected; however, the proteins required to initiate this cell death pathway are poorly understood. In this study, we show that UPR gene expression is induced in cells treated with ER stress agents in the presence or absence of murine caspase-12 or human caspase-4 expression and in cells that overexpress Bcl-x(L) or a dominant negative caspase-9. We further demonstrate that ER stress-induced apoptosis is a caspase-dependent process that does not require the expression of caspase-12 or caspase-4 but can be inhibited by overexpression of Bcl-x(L) or a dominant negative caspase-9. Additionally, treatment of human and murine cells with ER stress agents led to the cleavage of the caspase-4 fluorogenic substrate, LEVD-7-amino-4-trifluoromethylcoumarin, in the presence or absence of caspase-12 or caspase-4 expression, whereas Bcl-x(L) or a dominant negative caspase-9 overexpression inhibited LEVD-7-amino-4-trifluoromethylcoumarin cleavage. These data suggest that caspase-12 and caspase-4 are not required for the induction of ER stress-induced apoptosis and that caspase-4-like activity is not always associated with an initiating event.
Obeng
Esther A
EA
Department of Microbiology and Immunology, The University of Miami School of Medicine, Florida 33101, USA.
Boise
Lawrence H
LH
D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D053454:Caspase 12; D053453:Caspase 9; D020169:Caspases / Q000502:physiology*; D053471:Caspases, Initiator; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000502:physiology*; D006801:Humans; D051379:Mice; D017510:Protein Folding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D051020:bcl-X Protein
C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C506444:CASP12 protein, human; C506433:CASP9 protein, human; C506440:Casp12 protein, mouse; C101136:Casp4 protein, mouse; C506434:Casp9 protein, mouse; D053454:Caspase 12; D053453:Caspase 9; D020169:Caspases; D053471:Caspases, Initiator; D002118:Calcium