Seifert Anke, Düsterhöft Stefan, Wozniak Justyna, Koo Chek Z, Tomlinson Michael G, Nuti Elisa, Rossello Armando, Cuffaro Doretta, Yildiz Daniela, Ludwig Andreas
Institute of Molecular Pharmacology, Medical Faculty, RWTH Aachen University, Aachen, Germany.
School of Biosciences, University of Birmingham, Birmingham, UK.
Cell Mol Life Sci. 2021 Jan;78(2):715-732. doi: 10.1007/s00018-020-03507-w. Epub 2020 May 5.
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.
金属蛋白酶ADAM10对发育、炎症和癌症起着关键作用，并且可以被内源性或合成抑制剂所调控。在此，我们首次证明，通过抑制或功能丧失突变导致ADAM10的蛋白水解活性丧失，会促使该蛋白酶从细胞表面和整个细胞中被清除。这一过程依赖于温度，仅限于成熟的ADAM10，并且与内化增加、溶酶体降解以及成熟ADAM10在细胞外囊泡中的释放有关。从这种消耗中恢复需要从头合成。在功能上，这表现为ADAM10底物脱落的丧失和恢复。最后，对小鼠体内的ADAM10进行抑制会降低不同组织中的全身ADAM10水平。因此，ADAM10的活性对于其在体外和体内的表面表达至关重要。这些发现对于开发治疗性ADAM10抑制策略至关重要，并且可能展示了一种由于活性丧失而导致蛋白酶清除的新的生理相关机制。
