Bax and Bak can localize to the endoplasmic reticulum to initiate apoptosis.
Bax and Bak play a redundant but essential role in apoptosis initiated by the mitochondrial release of apoptogenic factors. In addition to their presence at the mitochondrial outer membrane, Bax and Bak can also localize to the ER. Agents that initiate ER stress responses can induce conformational changes and oligomerization of Bax on the ER as well as on mitochondria. In wild-type cells, this is associated with caspase 12 cleavage that is abolished in bax-/-bak-/- cells. In bax-/-bak-/- cells, introduction of Bak mutants selectively targeted to either mitochondria or the ER can induce apoptosis. However, ER-targeted, but not mitochondria-targeted, Bak leads to progressive depletion of ER Ca2+ and induces caspase 12 cleavage. In contrast, mitochondria-targeted Bak leads to enhanced caspase 7 and PARP cleavage in comparison with the ER-targeted Bak. These findings demonstrate that in addition to their functions at mitochondria, Bax and Bak also localize to the ER and function to initiate a parallel pathway of caspase activation and apoptosis.
Zong
Wei-Xing
WX
Department of Cancer Biology, Abramson Cancer Center, 421 Curie Blvd., BRB II/III, 445, Philadelphia, PA 19104-6160, USA. craig@mail.med.upenn.edu
Li
Chi
C
Hatzivassiliou
Georgia
G
Lindsten
Tullia
T
Yu
Qian-Chun
QC
Yuan
Junying
J
Thompson
Craig B
CB
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics; D053454:Caspase 12; D053179:Caspase 7; D020169:Caspases / Q000378:metabolism; D002461:Cell Line, Transformed; D004721:Endoplasmic Reticulum / Q000378:metabolism* / Q000648:ultrastructure; D005057:Eukaryotic Cells / Q000378:metabolism* / Q000648:ultrastructure; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011487:Protein Conformation; D021381:Protein Transport / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D013312:Stress, Physiological / Q000235:genetics / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein
C494773:Bak1 protein, mouse; C494827:Bax protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D011065:Poly(ADP-ribose) Polymerases; C506440:Casp12 protein, mouse; C505524:Casp7 protein, mouse; D053454:Caspase 12; D053179:Caspase 7; D020169:Caspases; D002118:Calcium