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.

中文翻译：

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金属蛋白酶ADAM10需要其活性来维持表面表达。

金属蛋白酶ADAM10关键地促进了发育，炎症和癌症，并可由内源性或合成抑制剂控制。在这里，我们首次证明通过抑制或功能突变引起的ADAM10蛋白水解活性的丧失诱导了蛋白酶从细胞表面和整个细胞中的去除。该过程是温度依赖性的，限于成熟的ADAM10，并且与增加的内在化，溶酶体降解以及成熟的ADAM10在细胞外囊泡中的释放相关。从这种消耗中恢复需要从头合成。在功能上，这可以通过ADAM10底物脱落的损失和恢复来反映。最后，对小鼠的ADAM10抑制作用会降低不同组织中的全身ADAM10水平。从而，ADAM10活性是其在体外和体内表面表达的关键条件。这些发现对于开发治疗性ADAM10抑制策略至关重要，并且可能展示由于活性丧失而引起的一种新型的生理学相关的蛋白酶去除机制。