KIF5B and KIF3A/KIF3B kinesins drive MT1-MMP surface exposure, CD44 shedding, and extracellular matrix degradation in primary macrophages
KIF5B and KIF3A/KIF3B kinesins drive MT1-MMP surface exposure, CD44 shedding, and extracellular matrix degradation in primary macrophages
复制标题
DOI：
10.1182/blood-2009-12-257089
复制
发表时间：
2010-09-02
期刊：
影响因子：
20.3
通讯作者：
Linder, Stefan
中科院分区：
文献类型：
--
作者：
Wiesner, Christiane;Faix, Jan;Linder, Stefan
基质金属蛋白酶（MMP）MT 1-MMP在白细胞生理学中起关键作用，如单核细胞渗出、树突状细胞迁移和T细胞归巢。MT 1-MMP是一种表面锚定的“主开关”蛋白酶，其切割多种底物，包括细胞外基质组分、基质受体以及其他MMP。然而，很少有人知道的机制，使细胞内运输和暴露的MT 1-MMP的细胞表面上。我们现在发现，在原代人巨噬细胞中，MT 1-MMP阳性囊泡在受KIF 5 B和KIF 3A/KIF 3B驱动蛋白调节的过程中沿沿着双向移动。siRNA诱导的敲除揭示了KIF 5 B和KIF 3A/KIF 3B的转运对于将MT 1-MMP递送至细胞表面以及MT 1-MMP的表面相关功能（例如基质受体CD 44和多配体蛋白聚糖-1的脱落或在足体处的细胞外基质的降解）是至关重要的。这些数据表明，驱动蛋白介导的MT 1-MMP的细胞内转运是一个关键的过程，使巨噬细胞动态修改其细胞周围环境。这些数据还确定了特定的驱动蛋白作为组织中MT 1-MMP活性的早期操纵的潜在靶标。（血。2010;116（9）：1559-1569）
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. (Blood. 2010;116(9):1559-1569)