Cancer cells break tissue barriers by use of small actin-rich membrane protrusions called invadopodia. Complete invadopodia maturation depends on protrusion outgrowth and the targeted delivery of the matrix metalloproteinase MT1-MMP via endosomal transport by mechanisms that are not known. Here, we show that the ER protein Protrudin orchestrates invadopodia maturation and function. Protrudin formed contact sites with MT1-MMP–positive endosomes that contained the RAB7-binding Kinesin-1 adaptor FYCO1, and depletion of RAB7, FYCO1, or Protrudin inhibited MT1-MMP–dependent extracellular matrix degradation and cancer cell invasion by preventing anterograde translocation and exocytosis of MT1-MMP. Moreover, when endosome translocation or exocytosis was inhibited by depletion of Protrudin or Synaptotagmin VII, respectively, invadopodia were unable to expand and elongate. Conversely, when Protrudin was overexpressed, noncancerous cells developed prominent invadopodia-like protrusions and showed increased matrix degradation and invasion. Thus, Protrudin-mediated ER–endosome contact sites promote cell invasion by facilitating translocation of MT1-MMP–laden endosomes to the plasma membrane, enabling both invadopodia outgrowth and MT1-MMP exocytosis.

中文翻译：

---

Protrudin介导的ER-内体接触位点促进MT1-MMP胞吐作用和细胞侵袭

癌细胞利用富含肌动蛋白的小膜突起（称为侵袭伪足）打破组织屏障。完整的侵袭伪足成熟取决于突出物的生长和基质金属蛋白酶 MT1-MMP 通过内体转运通过未知机制的靶向递送。在这里，我们证明 ER 蛋白 Protrudin 协调侵袭伪足的成熟和功能。Protrudin 与 MT1-MMP 阳性内体形成接触位点，该内体包含 RAB7 结合的驱动蛋白-1 接头 FYCO1，并且 RAB7、FYCO1 或 Protrudin 的耗竭通过防止顺行易位和癌细胞侵袭来抑制 MT1-MMP 依赖性细胞外基质降解和癌细胞侵袭。 MT1-MMP 的胞吐作用。此外，当内体易位或胞吐作用分别通过Protrudin或Synaptotagmin VII的消耗而受到抑制时，侵袭伪足无法扩张和伸长。相反，当 Protrudin 过度表达时，非癌细胞会出现明显的侵袭伪足样突起，并显示出基质降解和侵袭增加。因此，Protrudin 介导的 ER-内体接触位点通过促进 MT1-MMP 负载的内体易位至质膜来促进细胞侵袭，从而实现侵袭伪足生长和 MT1-MMP 胞吐作用。