An integrin beta-1-anchored bicaudal C1-polycystin-1 module essential for tubular morphogenesis in polycystic kidney disease

Abstract

Genetic variants in the RNA-binding protein bicaudal C1 (BICC1) have been linked to very-early-onset polycystic kidney disease (PKD). This study identifies a crucial integrin-beta1 (ITGB1)-BICC1-polycystin-1 (PC1) complex that regulates F-actin organization and cell adhesion in human kidney cells through the expression of filamin-binding-LIM-protein-1 (FBLIM1). Both Bicc1 and Pkd1 knockout cells exhibit abnormal F-actin structure, increased cell stiffness, decreased adhesion and impaired migration while inhibiting F-actin branching directly triggers cyst formation. Locally, BICC1 interacts with F-actin, ITGB1, and FBLIM1 at focal adhesions. ITGB1 knockdown reduces surface BICC1 expression. In turn, BICC1 stabilizes FBLIM1 by influencing transcript abundance, promoting its local translation, and protecting it from degradation in the presence of PC1. In summary, these findings reveal a novel model of cystogenesis linking BICC1's dual RNA and protein regulatory functions to the maintenance of cytoskeletal and tubular integrity.