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.
Sbai
Oualid
O
Neurobiologie des Interactions Cellulaires et Neurophysiopathologie, UMR 6184 CNRS--Université de la Méditerranée, Faculté de Médecine, 51 Boulevard Pierre Dramard, Marseille Cedex 15, France.
Ould-Yahoui
Adlane
A
Ferhat
Lotfi
L
Gueye
Yatma
Y
Bernard
Anne
A
Charrat
Eliane
E
Mehanna
Ali
A
Risso
Jean-Jacques
JJ
Chauvin
Jean-Paul
JP
Fenouillet
Emmanuel
E
Rivera
Santiago
S
Khrestchatisky
Michel
M
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