基质金属蛋白酶MT1-MMP是细胞蛋白溶解的核心效应因子。因此，MT1-MMP在细胞迁移和侵袭过程中的表面定位池的调控对于细胞非常重要。本研究识别了超进程型动力蛋白KIF16B作为快速回收MT1-MMP到初代人类巨噬细胞表面的主要驱动因素。KIF16B与MT1-MMP形成复合物存在于Rab14阳性小泡中，当KIF16B耗尽时，通过显微镜、生物化学和细胞分选方法的研究结果显示，MT1-MMP表面水平显著降低。因此，KIF16B耗尽的巨噬细胞表现出严重降低的基质降解和侵袭能力。我们进一步发现，KIF16B的货物结合C-末端是MT1-MMP转运的关键，其过量表达可将MT1-MMP小泡与内源性驱动机解耦，从而导致表面相关的MT1-MMP水平降低，并减少基质降解和侵袭。重要的是，对原代巨噬细胞中KIF16B的耗竭还会降低肿瘤球体中癌细胞的共侵入能力，这表明巨噬细胞中的KIF16B驱动的回收途径是肿瘤微环境中的一个重要调控因素。© 2023 Hey et al.

The matrix metalloproteinase MT1-MMP is a central effector of cellular proteolysis. Accordingly, regulation of the surface-localized pool of MT1-MMP is crucial for cell migration and invasion. Here, we identify the superprocessive kinesin KIF16B as a major driver of fast recycling of MT1-MMP to the surface of primary human macrophages. KIF16B associates with MT1-MMP on Rab14-positive vesicles, and its depletion results in strongly reduced MT1-MMP surface levels, as shown by microscopical, biochemical, and cell-sorting approaches. As a consequence, KIF16B-depleted macrophages exhibit strongly reduced matrix degradation and invasion. We further identify the cargo-binding C-terminus of KIF16B as a critical element of MT1-MMP transport, as its overexpression uncouples MT1-MMP vesicles from the endogenous motor, thus leading to a reduction of surface-associated MT1-MMP and to reduced matrix degradation and invasion. Importantly, depletion of KIF16B in primary macrophages also reduces the co-invasion of cancer cells from tumor spheroids, pointing to the KIF16B-driven recycling pathway in macrophages as an important regulatory element of the tumor microenvironment.© 2023 Hey et al.