Deubiquitinase USP10 regulates Notch signaling in the endothelium

Notch signaling is a core patterning module for vascular morphogenesis that codetermines the sprouting behavior of endothelial cells (ECs). Tight quantitative and temporal control of Notch activity is essential for vascular development, yet the details of Notch regulation in ECs are incompletely understood. We found that ubiquitin-specific peptidase 10 (USP10) interacted with the NOTCH1 intracellular domain (NICD1) to slow the ubiquitin-dependent turnover of this short-lived form of the activated NOTCH1 receptor. Accordingly, inactivation of USP10 reduced NICD1 abundance and stability and diminished Notch-induced target gene expression in ECs. In mice, the loss of endothelial Usp10 increased vessel sprouting and partially restored the patterning defects caused by ectopic expression of NICD1. Thus, USP10 functions as an NICD1 deubiquitinase that fine-tunes endothelial Notch responses during angiogenic sprouting. This work is supported by the Max Planck Society, European Research Council (ERC) starting grant ANGIOMET (311546), ERC consolidator grant EMERGE (773047), the Deutsche Forschungsgemeinschaft (SFB 834), the Excellence Cluster Cardiopulmonary System (EXC 147/1), LOEWE grant Ub-Net, the DZHK (German Center for Cardiovascular Research), the Stiftung Charité, the Cardio-Pulmonary Institute (EXC 2026 project ID 390649896), and the European Molecular Biology Organization (EMBO) Young Investigator Programme Sí