The Role of the Co-Chaperone DNAJB11 in Polycystic Kidney Disease: Molecular Mechanisms and Cellular Origin of Cyst Formation

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in the genes PKD1 and PKD2, encoding the membrane proteins polycystin-1 (PC1) and polycystin-2 (PC2). PC1 and PC2 form a receptor-ion channel complex that is required for the regulation of the renal tubular diameter. Loss of polycystin function results in cyst formation from epithelial cells of all nephron segments. Atypical forms of ADPKD are caused by mutations in genes encoding endoplasmic reticulum (ER)-resident proteins through pathogenic mechanisms that are not well understood. Here, we investigate the function of DNAJB11, an endoplasmic reticulum (ER) co-chaperone associated with atypical ADPKD. Mouse models with constitutive and conditional Dnajb11 inactivation as well as Dnajb11-deficient renal epithelial cells were generated to investigate the genetic mechanism underlying autosomal dominant inheritance, the specific cell types driving cyst formation, and molecular mechanisms underlying DNAJB11-dependent polycystic kidney disease. We show that biallelic loss of Dnajb11 causes cystic kidney disease and fibrosis, mirroring human disease characteristics. In contrast to classical ADPKD, cysts predominantly originate from proximal tubules. Cyst formation begins in utero and the timing of Dnajb11 inactivation influences disease severity. Furthermore, impaired PC1 cleavage is identified as a potential mechanism underlying DNAJB11-dependent cyst formation. Quantitative proteomic analysis of Dnajb11- and Pkd1-deficient cells reveals common and distinct pathways and dysregulated proteins, which may help to better understand phenotypic differences between different forms of ADPKD. ### Competing Interest Statement The authors have declared no competing interest.