USP40 protects podocytes by deubiquitylating integrin β1

Area of Science:

• Nephrology
• Molecular Biology
• Cell Biology

Background:

• Focal segmental glomerulosclerosis (FSGS) involves podocyte injury, but mechanisms remain unclear.
• Podocyte detachment and loss are critical in FSGS pathogenesis.
• Integrin β1 is vital for podocyte adhesion to the glomerular basement membrane.

Purpose of the Study:

• To investigate the role of ubiquitin-specific protease 40 (USP40) in podocytes.
• To determine USP40's effect on the adhesion molecule integrin β1.
• To explore the USP40-integrin β1 axis as a potential therapeutic target for FSGS.

Main Methods:

• Utilized USP40 knockout mice in an experimental FSGS model.
• Performed USP40 knockdown in cultured podocytes.
• Investigated integrin β1 ubiquitination and endocytosis in HEK293 cells and mouse podocytes.

Main Results:

• USP40 knockout mice showed exacerbated proteinuria, glomerulosclerosis, and reduced podocyte number and integrin β1 expression.
• USP40 knockdown in podocytes decreased integrin β1 expression and impaired cell adhesion.
• USP40 suppressed integrin β1 monoubiquitylation and prevented its clathrin-mediated endocytosis.

Conclusions:

• USP40 stabilizes integrin β1 at the podocyte plasma membrane by inhibiting its endocytosis.
• The USP40-integrin β1 pathway is crucial for maintaining podocyte adhesion.
• Targeting the USP40-integrin β1 axis may offer a novel therapeutic strategy for FSGS.