KIF16B drives MT1-MMP recycling in macrophages and promotes co-invasion of cancer cells

Life Sci Alliance. 2023 Sep 11;6(11):e202302158. doi: 10.26508/lsa.202302158. Print 2023 Nov.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Movement / genetics
  • Cell Separation
  • Humans
  • Kinesins* / genetics
  • Macrophages
  • Matrix Metalloproteinase 14* / genetics
  • Neoplasms*
  • rab GTP-Binding Proteins / genetics

Substances

  • KIF16B protein, human
  • Kinesins
  • Matrix Metalloproteinase 14
  • rab GTP-Binding Proteins
  • Rab14 protein, human
  • MMP14 protein, human