2. Academic Validation
  3. The metalloproteinase ADAM10 requires its activity to sustain surface expression

The metalloproteinase ADAM10 requires its activity to sustain surface expression

  • Cell Mol Life Sci. 2021 Jan;78(2):715-732. doi: 10.1007/s00018-020-03507-w.
Anke Seifert 1,  Stefan Düsterhöft 1,  Justyna Wozniak 1,  Chek Z Koo 2,  Michael G Tomlinson 2,  Elisa Nuti 3,  Armando Rossello 3,  Doretta Cuffaro 3,  Daniela Yildiz 1 4,  Andreas Ludwig 5 6
Affiliations

Affiliations

  • 1 Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
  • 2 School of Biosciences, University of Birmingham, Birmingham, UK.
  • 3 Department of Pharmacy, University of Pisa, Pisa, Italy.
  • 4 Institute of Experimental and Clinical Pharmacology and Toxicology, PZMS, ZHMB, Saarland University, Homburg, Germany.
  • 5 Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany. [email protected].
  • 6 Institute of Pharmacology and Toxicology, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany. [email protected].
PMID: 32372373 DOI: 10.1007/s00018-020-03507-w
Abstract

The metalloproteinase ADAM10 critically contributes to development, inflammation, and Cancer and can be controlled by endogenous or synthetic inhibitors. Here, we demonstrate for the first time that loss of proteolytic activity of ADAM10 by either inhibition or loss of function mutations induces removal of the protease from the cell surface and the whole cell. This process is temperature dependent, restricted to mature ADAM10, and associated with an increased internalization, lysosomal degradation, and release of mature ADAM10 in extracellular vesicles. Recovery from this depletion requires de novo synthesis. Functionally, this is reflected by loss and recovery of ADAM10 substrate shedding. Finally, ADAM10 inhibition in mice reduces systemic ADAM10 levels in different tissues. Thus, ADAM10 activity is critically required for its surface expression in vitro and in vivo. These findings are crucial for development of therapeutic ADAM10 inhibition strategies and may showcase a novel, physiologically relevant mechanism of protease removal due to activity loss.

Keywords

ADAM10; Extracellular vesicles; Inflammation; Metalloproteinase; Shedding.

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