Endoplasmic reticulum stress induces apoptosis by an apoptosome-dependent but caspase 12-independent mechanism.
The endoplasmic reticulum (ER) is the cellular site of polypeptide folding and modification. When these processes are hampered, an unfolded protein response (UPR) is activated. If the damage is too broad, the mammalian UPR launches the apoptotic program. As a consequence, mobilization of ER calcium stores sensitizes mitochondria to direct proapoptotic stimuli. We make use of a mouse Apaf1-deficient cell system of proneural origin to understand the roles played in this context by the apoptosome, the most studied apoptotic machinery along the mitochondrial pathway of death. We show here that in the absence of the apoptosome ER stress induces cytochrome c release from the mitochondria but that apoptosis cannot occur. Under these circumstances, Grp78/BiP and GADD153/CHOP, both hallmarks of UPR, are canonically up-regulated, and calcium is properly released from ER stores. We also demonstrate that caspase 12, a protease until now believed to play a central role in the initiation of ER stress-induced cell death in the mouse system, is dispensable for the mitochondrial pathway of death to take place.
Di Sano
Federica
F
Department of Biology, University of Tor Vergata.
Ferraro
Elisabetta
E
Tufi
Roberta
R
Achsel
Tilmann
T
Piacentini
Mauro
M
Cecconi
Francesco
F
D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000502:physiology; D053477:Apoptotic Protease-Activating Factor 1; D002118:Calcium / Q000378:metabolism; D053454:Caspase 12; D020169:Caspases / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D024101:Mitochondrial Proteins / Q000502:physiology; D018832:Molecular Chaperones; D018384:Oxidative Stress / Q000502:physiology*; D011506:Proteins / Q000502:physiology*; D051742:Transcription Factor CHOP
C506593:Apaf1 protein, mouse; D051017:Apoptosis Regulatory Proteins; D053477:Apoptotic Protease-Activating Factor 1; C497250:Ddit3 protein, mouse; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D011506:Proteins; D051742:Transcription Factor CHOP; C506440:Casp12 protein, mouse; D053454:Caspase 12; D020169:Caspases; D002118:Calcium