S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death.
Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of neurodegenerative diseases and stroke. However, the mechanism of MMP activation remains unclear. We report that MMP activation involves S-nitrosylation. During cerebral ischemia in vivo, MMP-9 colocalized with neuronal nitric oxide synthase. S-Nitrosylation activated MMP-9 in vitro and induced neuronal apoptosis. Mass spectrometry identified the active derivative of MMP-9, both in vitro and in vivo, as a stable sulfinic or sulfonic acid, whose formation was triggered by S-nitrosylation. These findings suggest a potential extracellular proteolysis pathway to neuronal cell death in which S-nitrosylation activates MMPs, and further oxidation results in a stable posttranslational modification with pathological activity.
Center for Neuroscience and Aging, Program in Cell Adhesion and Extracellular Matrix Biology, The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
Zezong
Z
Gu
Marcus
M
Kaul
Boxu
B
Yan
Steven J
SJ
Kridel
Jiankun
J
Cui
Alex
A
Strongin
Jeffrey W
JW
Smith
Robert C
RC
Liddington
Stuart A
SA
Lipton
D000818:Animals; D017209:Apoptosis; D002545:Brain Ischemia / Q000201:enzymology* / Q000473:pathology; D002460:Cell Line; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004789:Enzyme Activation; D004792:Enzyme Precursors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008958:Models, Molecular; D009474:Neurons / Q000502:physiology*; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D010084:Oxidation-Reduction; D010662:Phenylmercuric Acetate / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D015424:Reperfusion; D026403:S-Nitrosothiols / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
D004792:Enzyme Precursors; D011994:Recombinant Proteins; D026403:S-Nitrosothiols; D009569:Nitric Oxide; C010024:4-aminophenylmercuriacetate; C021315:S-nitrosocysteine; C496320:NOS1 protein, human; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; C496322:Nos1 protein, rat; D020780:Matrix Metalloproteinase 9; D003545:Cysteine; D010662:Phenylmercuric Acetate