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, or T-cell homing. MT1-MMP is a surface-anchored "master switch" proteinase that cleaves a variety of substrates including extracellular matrix (ECM) 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. They also identify specific kinesins as potential targets for the early manipulation of MT1-MMP activity in tissues.