Inflammatory proprotein convertase-matrix metalloproteinase proteolytic pathway in antigen-presenting cells as a step to autoimmune multiple sclerosis.
Multiple sclerosis (MS) is a disease of the central nervous system with autoimmune etiology. Susceptibility to MS is linked to viral and bacterial infections. Matrix metalloproteinases (MMPs) play a significant role in the fragmentation of myelin basic protein (MBP) and demyelination. The splice variants of the single MBP gene are expressed in the oligodendrocytes of the central nervous system (classic MBP) and in the immune cells (Golli-MBPs). Our data suggest that persistent inflammation caused by environmental risk factors is a step to MS. We have discovered biochemical evidence suggesting the presence of the inflammatory proteolytic pathway leading to MS. The pathway involves the self-activated furin and PC2 proprotein convertases and membrane type-6 MMP (MT6-MMP/MMP-25) that is activated by furin/PC2. These events are followed by MMP-25 proteolysis of the Golli-MBP isoforms in the immune system cells and stimulation of the specific autoimmune T cell clones. It is likely that the passage of these autoimmune T cell clones through the disrupted blood-brain barrier to the brain and the recognition of neuronal, classic MBP causes inflammation leading to the further up-regulation of the activity of the multiple individual MMPs, the massive cleavage of MBP in the brain, demyelination, and MS. In addition to the cleavage of Golli-MBPs, MMP-25 proteolysis readily inactivates crystallin alphaB that is a suppressor of MS. These data suggest that MMP-25 plays an important role in MS pathology and that MMP-25, especially because of its restricted cell/tissue expression pattern and cell surface/lipid raft localization, is a promising drug target in MS.
Shiryaev
Sergey A
SA
Burnham Institute for Medical Research, La Jolla, California 92037, USA.
Remacle
Albert G
AG
Savinov
Alexei Y
AY
Chernov
Andrei V
AV
Cieplak
Piotr
P
Radichev
Ilian A
IA
Williams
Roy
R
Shiryaeva
Tatiana N
TN
Gawlik
Katarzyna
K
Postnova
Tatiana I
TI
Ratnikov
Boris I
BI
Eroshkin
Alexei M
AM
Motamedchaboki
Khatereh
K
Smith
Jeffrey W
JW
Strongin
Alex Y
AY
D000938:Antigen-Presenting Cells / Q000378:metabolism / Q000473:pathology*; D001921:Brain / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D058851:GPI-Linked Proteins; D006801:Humans; D007249:Inflammation / Q000201:enzymology* / Q000209:etiology; D053504:Matrix Metalloproteinases, Membrane-Associated / Q000235:genetics / Q000378:metabolism*; D021962:Membrane Microdomains; D009103:Multiple Sclerosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004676:Myelin Basic Protein / Q000378:metabolism; D043484:Proprotein Convertases / Q000378:metabolism*; D015398:Signal Transduction; D014018:Tissue Distribution; D015854:Up-Regulation
D058851:GPI-Linked Proteins; D004676:Myelin Basic Protein; D043484:Proprotein Convertases; D053504:Matrix Metalloproteinases, Membrane-Associated; C403928:matrix metalloproteinase 25