Ubiquitous calpains promote caspase-12 and JNK activation during endoplasmic reticulum stress-induced apoptosis.
Ubiquitously expressed mu- and m-calpain proteases are implicated in development and apoptosis. They consist of 80-kDa catalytic subunits encoded by the capn1 and capn2 genes, respectively, and a common 28-kDa regulatory subunit encoded by the capn4 gene. The regulatory subunit is required to maintain the stability and activity of mu- and m-calpains. Accordingly, genetic disruption of capn4 in the mouse eliminated both ubiquitous calpain activities. In embryonic fibroblasts derived from these mice, calpain deficiency correlated with resistance to endoplasmic reticulum (ER) stress-induced apoptosis, and this was directly related to a calpain requirement for activation of both caspase-12 and the ASK1-JNK cascade. This study provides compelling genetic evidence for calpain's role in caspase-12 activation at the ER, and reveals a novel role for the ubiquitous calpains in ER-stress induced apoptosis and JNK activation.
Tan
Yinfei
Y
Division of Cancer Biology and Genetics, Queen's University Cancer Research Institute, Kingston, Ontario, Canada.
Dourdin
Nathalie
N
Wu
Chao
C
De Veyra
Teresa
T
Elce
John S
JS
Greer
Peter A
PA
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002154:Calpain / Q000502:physiology*; D053454:Caspase 12; D020169:Caspases / Q000378:metabolism*; D017931:DNA Primers; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D004789:Enzyme Activation; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D018384:Oxidative Stress
D017931:DNA Primers; D048670:MAP Kinase Kinase 4; D002154:Calpain; C506440:Casp12 protein, mouse; D053454:Caspase 12; D020169:Caspases