Institut für Medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Eppendorf, Hamburg, Germany.
Institut für Medizinische Mikrobiologie, Virologie und Hygiene, Universitätsklinikum Eppendorf, Hamburg, Germany
Life Sci Alliance. 2023 Sep 11;6(11). doi: 10.26508/lsa.202302158. Print 2023 Nov.
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.
基质金属蛋白酶 MT1-MMP 是细胞蛋白水解的核心效应物。因此，表面定位的 MT1-MMP 池的调节对于细胞迁移和侵袭至关重要。在这里，我们确定超动力驱动蛋白 KIF16B 是将 MT1-MMP 快速回收至原代人巨噬细胞表面的主要驱动因素。KIF16B 与 Rab14 阳性囊泡上的 MT1-MMP 相关联，其耗竭导致 MT1-MMP 表面水平明显降低，这通过显微镜、生化和细胞分选方法得到证实。结果，KIF16B 耗尽的巨噬细胞表现出明显降低的基质降解和侵袭。我们进一步确定 KIF16B 的货物结合 C 末端是 MT1-MMP 运输的关键元件，因为其过表达使 MT1-MMP 囊泡与内源性马达解耦，从而导致表面相关的 MT1-MMP 减少，并降低基质降解和侵袭。重要的是，在原代巨噬细胞中耗尽 KIF16B 也会减少肿瘤球体中癌细胞的共同侵袭，这表明巨噬细胞中 KIF16B 驱动的回收途径是肿瘤微环境的重要调节元件。
