The mechanisms leading to the formation of sclerotic lesions in focal segmental glomerulosclerosis (FSGS) remain incompletely understood; however, podocyte detachment and loss are considered key pathogenic events. Ubiquitin-specific protease 40 (USP40) is a deubiquitylating enzyme expressed in podocytes. In the present study, we investigated the role of USP40 in podocytes, focusing on its impact on the adhesion molecule integrin β1, which is essential for anchoring podocytes to the glomerular basement membrane. When USP40 knockout mice were subjected to an experimental FSGS model, they exhibited significantly more severe proteinuria and glomerulosclerosis than control mice, along with a marked reduction in podocyte number and integrin β1 expression. Consistently, knockdown of USP40 in cultured podocytes resulted in decreased integrin β1 expression and impaired adhesive properties compared with sham-treated cells. In HEK293 cells transfected with ubiquitin constructs, USP40 suppressed integrin β1 monoubiquitylation. In a separate internalization assay, USP40 prevented the clathrin-mediated endocytosis of integrin β1. In USP40 knockout mice, clathrin-coated vesicles colocalizing with integrin β1 were more frequently observed in podocyte foot processes than in control mice. Together, these findings suggest that USP40 functions as a deubiquitylating enzyme that stabilizes integrin β1 at the podocyte plasma membrane by preventing its endocytosis. We therefore propose that the USP40-integrin β1 axis represents a potential therapeutic target for FSGS.
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