Invasion by activated macrophages requires delivery of nascent membrane-type-1 matrix metalloproteinase through late endosomes/lysosomes to the cell surface

Joan Röhl, Zoe E. West, Maren Rudolph, Andreea Zaharia, Derek Van Lonkhuyzen, Danica K. Hickey, Annalese B.T. Semmler, Rachael Z. Murray*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)661-673
Number of pages13
JournalTraffic
Volume20
Issue number9
DOIs
Publication statusPublished - Sep 2019
Externally publishedYes

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