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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.
Original language | English |
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Pages (from-to) | 715-732 |
Number of pages | 18 |
Journal | Cellular and Molecular Life Sciences |
Volume | 78 |
Issue number | 2 |
Early online date | 5 May 2020 |
DOIs | |
Publication status | Published - Jan 2021 |
Keywords
- ADAM10 Protein/analysis
- Amyloid Precursor Protein Secretases/analysis
- Animals
- Cell Line
- Cell Membrane/genetics
- Extracellular Vesicles/genetics
- Humans
- Loss of Function Mutation
- Male
- Membrane Proteins/analysis
- Mice, Inbred C57BL
- Proteolysis
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