KIF5B and KIF3A/KIF3B kinesins drive MT1-MMP surface exposure, CD44 shedding, and extracellular matrix degradation in primary macrophages.
The matrix metalloproteinase (MMP) MT1-MMP plays pivotal roles in leukocyte physiology such as monocyte diapedesis, dendritic cell migration, and T-cell homing. MT1-MMP is a surface-anchored "master switch" proteinase that cleaves a variety of substrates including extracellular matrix components, matrix receptors, and also other MMPs. However, little is known about the mechanisms enabling intracellular trafficking and exposure of MT1-MMP on the cell surface. We now show that, in primary human macrophages, MT1-MMP-positive vesicles travel bidirectionally along microtubules, in a process regulated by KIF5B and KIF3A/KIF3B kinesins. SiRNA-induced knockdown revealed that transport by KIF5B and KIF3A/KIF3B is crucial for delivery of MT1-MMP to the cell surface and also for surface-associated functions of MT1-MMP, such as shedding of the matrix receptors CD44 and syndecan-1 or degradation of extracellular matrix at podosomes. These data show that kinesin-mediated intracellular transport of MT1-MMP is a pivotal process that allows macrophages to dynamically modify their pericellular environment. These data also identify specific kinesins as potential targets for the early manipulation of MT1-MMP activity in tissues.
Wiesner
Christiane
C
Institute for Medical Microbiology, Virology and Hygiene, University Medical Center Eppendorf, Hamburg, Germany.
Faix
Jan
J
Himmel
Mirko
M
Bentzien
Frank
F
Linder
Stefan
S
D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000378:metabolism; D010957:Plasmids; D053668:Syndecan-1 / Q000378:metabolism
C497483:CD44 protein, human; D018960:Hyaluronan Receptors; C087415:KIF3A protein, human; C095899:KIF3B protein, human; C488101:KIF5B protein, human; C508241:SDC1 protein, human; D053668:Syndecan-1; D053511:Matrix Metalloproteinase 14; D016547:Kinesins