Differential vesicular distribution and trafficking of MMP-2, MMP-9, and their inhibitors in astrocytes.
Astrocytes play an active role in the central nervous system and are critically involved in astrogliosis, a homotypic response of these cells to disease, injury, and associated neuroinflammation. Among the numerous molecules involved in these processes are the matrix metalloproteinases (MMPs), a family of zinc-dependent endopeptidases, secreted or membrane-bound, that regulate by proteolytic cleavage the extracellular matrix, cytokines, chemokines, cell adhesion molecules, and plasma membrane receptors. MMP activity is tightly regulated by the tissue inhibitors of MMPs (TIMPs), a family of secreted multifunctional proteins. Astrogliosis in vivo and astrocyte reactivity induced in vitro by proinflammatory cues are associated with modulation of expression and/or activity of members of the MMP/TIMP system. However, nothing is known concerning the intracellular distribution and secretory pathways of MMPs and TIMPs in astrocytes. Using a combination of cell biology, biochemistry, fluorescence and electron microscopy approaches, we investigated in cultured reactive astrocytes the intracellular distribution, transport, and secretion of MMP-2, MMP-9, TIMP-1, and TIMP-2. MMP-2 and MMP-9 demonstrate nuclear localization, differential intracellular vesicular distribution relative to the myosin V and kinesin molecular motors, and LAMP-2-labeled lysosomal compartment, and we show vesicular secretion for MMP-2, MMP-9, and their inhibitors. Our results suggest that these proteinases and their inhibitors use different pathways for trafficking and secretion for distinct astrocytic functions.
Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, UMR 6184 CNRS--Université de la Méditerranée, Faculté de Médecine, 51 Boulevard Pierre Dramard, Marseille Cedex 15, France.
Oualid
O
Sbai
Adlane
A
Ould-Yahoui
Lotfi
L
Ferhat
Yatma
Y
Gueye
Anne
A
Bernard
Eliane
E
Charrat
Ali
A
Mehanna
Jean-Jacques
JJ
Risso
Jean-Paul
JP
Chauvin
Emmanuel
E
Fenouillet
Santiago
S
Rivera
Michel
M
Khrestchatisky
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000201:enzymology* / Q000648:ultrastructure; D002451:Cell Compartmentation / Q000502:physiology; D002478:Cells, Cultured; D004660:Encephalitis / Q000201:enzymology* / Q000503:physiopathology; D005911:Gliosis / Q000201:enzymology* / Q000503:physiopathology; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D020409:Molecular Motor Proteins / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D022161:Transport Vesicles / Q000201:enzymology* / Q000648:ultrastructure
D052119:Lysosomal-Associated Membrane Protein 2; D020409:Molecular Motor Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9