Caspase-4 is partially cleaved by calpain via the impairment of Ca2+ homeostasis under the ER stress.
In the previous reports, we showed that caspase-4, which has high homology to caspase-12, plays an important role in the neural cell death via the endoplasmic reticulum (ER) stress. In addition, we elucidated the involvement of the familial Alzheimer's disease (AD)-linked presenilin-1 (PS1) mutation and beta-amyloid induced-apoptotic signaling in human neural cells in the activation (cleavage) of caspase-4. These results suggest the involvement of caspase-4 in the cell death observed in AD. To elucidate the mechanism of the cleavage of caspase-4 under ER stress, we used EGTA, a Ca(2+) chelator, because the cleavage caspase-12 has reported to be regulated by the calpain. As the results, EGTA inhibited the cleavage of caspase-4 in a concentration-dependent manner. In addition, inhibitors of calpain, which are activated by the Ca(2+), also inhibited the cleavage of caspase-4. Furthermore, EGTA and caplain inhibitors rescued the neural cell death under the ER stress. These results suggest that the disturbance of Ca(2+) homeostasis induced by ER stress should cause the activation of caspase-4 resulting in the neural cell death.
Matsuzaki
Shinsuke
S
Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University,Suita, Osaka, Japan. s-matsuzaki@anat2.med.osaka-u.ac.jp
Hiratsuka
Toru
T
Kuwahara
Ryusuke
R
Katayama
Taiichi
T
Tohyama
Masaya
M
D002118:Calcium / Q000378:metabolism*; D002154:Calpain / Q000378:metabolism*; D053471:Caspases, Initiator / Q000378:metabolism*; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006706:Homeostasis; D006801:Humans; D006868:Hydrolysis; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D014415:Tunicamycin; D004533:Egtazic Acid; D019284:Thapsigargin; C093516:CASP4 protein, human; D002154:Calpain; D053471:Caspases, Initiator; D002118:Calcium