Protrudin-mediated ER-endosome contact sites promote MT1-MMP exocytosis and cell invasion

• Published in: The Journal of cell biology 2020-08, Vol.219 (8), p.1
• Main Authors: Pedersen, Nina Marie, Wenzel, Eva Maria, Wang, Ling, Antoine, Sandra, Chavrier, Philippe, Stenmark, Harald, Raiborg, Camilla
• Format: Article
• Language: English
• Subjects: Actin; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cancer; Cell Line, Tumor; Cell Movement; Cellular Biology; Degradation; Depletion; Endoplasmic Reticulum - enzymology; Endoplasmic Reticulum - genetics; Endoplasmic Reticulum - pathology; Endosomes; Endosomes - enzymology; Endosomes - genetics; Endosomes - pathology; Exocytosis; Extracellular matrix; Extracellular Matrix - enzymology; Extracellular Matrix - pathology; Female; Gene Expression Regulation, Neoplastic; Humans; Kinesin; Life Sciences; Matrix metalloproteinase; Matrix Metalloproteinase 14 - genetics; Matrix Metalloproteinase 14 - metabolism; Matrix metalloproteinases; Maturation; Membranes; Metalloproteinase; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Neoplasm Invasiveness; Podosomes - enzymology; Podosomes - genetics; Podosomes - pathology; Protein Transport; rab GTP-Binding Proteins - genetics; rab GTP-Binding Proteins - metabolism; Signal Transduction; Synaptotagmin; Synaptotagmins - genetics; Synaptotagmins - metabolism; Trafficking; Translocation; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.202003063

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.