Matrix metalloproteinase-3 is increased and participates in neuronal apoptotic signaling downstream of caspase-12 during endoplasmic reticulum stress.
Although endoplasmic reticulum (ER) stress-induced apoptosis has been associated with pathogenesis of neurodegenerative diseases, the cellular components involved have not been well delineated. The present study shows that matrix metalloproteinase (MMP)-3 plays a role in the ER stress-induced apoptosis. ER stress induced by brefeldin A (BFA) or tunicamycin (TM) increases gene expression of MMP-3, selectively among various MMP subtypes, and the active form of MMP-3 (actMMP-3) in the brain-derived CATH.a cells. Pharmacological inhibition of enzyme activity, small interference RNA-mediated gene knockdown, and gene knock-out of MMP-3 all provide protection against ER stress. MMP-3 acts downstream of caspase-12, because both pharmacological inhibition and gene knockdown of caspase-12 attenuate the actMMP-3 increase, but inhibition and knock-out of MMP-3 do not alter caspase-12. Furthermore, independently of the increase in the protein level, the catalytic activity of MMP-3 enzyme can be increased via lowering of its endogenous inhibitor protein TIMP-1. Caspase-12 causes liberation of MMP-3 enzyme activity by degrading TIMP-1 that is already bound to actMMP-3. TIMP-1 is decreased in response to ER stress, and TIMP-1 overexpression leads to cell protection and a decrease in MMP-3 activity. Taken together, actMMP-3 protein level and catalytic activity are increased following caspase-12 activation during ER stress, and this in turn plays a role in the downstream apoptotic signaling in neuronal cells. MMP-3 and TIMP-1 may therefore serve as cellular targets for therapy against neurodegenerative diseases.
Kim
Eun-Mee
EM
Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Asan Institute for Life Science, Seoul 138-736, Korea.
Shin
Eun-Jung
EJ
Choi
Ji Hyun
JH
Son
Hyo Jin
HJ
Park
Il-Seon
IS
Joh
Tong H
TH
Hwang
Onyou
O
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D017209:Apoptosis; D020126:Brefeldin A / Q000494:pharmacology; D053454:Caspase 12 / Q000096:biosynthesis*; D004721:Endoplasmic Reticulum / Q000201:enzymology* / Q000378:metabolism; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis; D014415:Tunicamycin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D019715:Tissue Inhibitor of Metalloproteinase-1; D014415:Tunicamycin; D020126:Brefeldin A; D053454:Caspase 12; D019278:Matrix Metalloproteinase 3