USP40

Deubiquitinating enzyme that plays a key role in maintaining endothelial cell (EC) barrier integrity and regulating apoptosis and inflammation. Stabilizes Claudin-1/CLDN1 by cleaving its polyubiquitin chains, thereby protecting tight junction structure. Prevents EC barrier disruption by inhibiting RhoA activation and reducing phosphorylation of myosin light chain and cofilin. Suppresses EC inflammation by inhibiting NF-kappa-B activation, decreasing ICAM1 expression, and reducing leukocyte adhesion to ECs. Mediates these protective effects in part via deubiquitination and inactivation of heat shock protein 90-beta/HSP90AB1. Targets CFLAR for 'Lys-48'-linked deubiquitination, stabilizing its protein levels. This interaction is facilitated by the adapter protein GMEB1, which enhances USP40-CFLAR binding. Through CFLAR stabilization, USP40 inhibits pro-caspase-8 activation and protects against apoptosis. Additionally, USP40 stabilizes HINT1, an activator of p53/TP53, thereby maintaining p53/TP53 levels and sustaining the HINT1-p53/TP53 axis (By similarity)..

Function from UniProtKB (Q9NVE5), read 2026-09-23. CC BY 4.0.