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Invasion by activated macrophages requires delivery of nascent membrane‐type‐1 matrix metalloproteinase through late endosomes/lysosomes to the cell surface
Authors:Joan R  hl,Zoe E. West,Maren Rudolph,Andreea Zaharia,Derek Van Lonkhuyzen,Danica K. Hickey,Annalese B. T. Semmler,Rachael Z. Murray
Affiliation:Joan Röhl,Zoe E. West,Maren Rudolph,Andreea Zaharia,Derek Van Lonkhuyzen,Danica K. Hickey,Annalese B. T. Semmler,Rachael Z. Murray
Abstract:Macrophage migration into injured or infected tissue is a key aspect in the pathophysiology of many diseases where inflammation is a driving factor. Membrane‐type‐1 matrix metalloproteinase (MT1‐MMP) cleaves extracellular matrix components to facilitate invasion. Here we show that, unlike the constitutive MT1‐MMP surface recycling seen in cancer cells, unactivated macrophages express low levels of MT1‐MMP. Upon lipopolysaccharide (LPS) activation, MT1‐MMP synthesis dramatically increases 10‐fold at the surface by 15 hours. MT1‐MMP is trafficked from the Golgi complex to the surface via late endosomes/lysosomes in a pathway regulated by the late endosome/lysosome R‐SNAREs VAMP7 and VAMP8. These form two separate complexes with the surface Q‐SNARE complex Stx4/SNAP23 to regulate MT1‐MMP delivery to the plasma membrane. Loss of either one of these SNAREs leads to a reduction in surface MT1‐MMP, gelatinase activity and reduced invasion. Thus, inhibiting MT1‐MMP transport through this pathway could reduce macrophage migration and the resulting inflammation.
Keywords:late endosome  macrophage  migration  MT1‐MMP  SNAP23  SNARE  Stx4  VAMP7  VAMP8
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