Genetic mechanism of autosomal dominant polycystic liver disease (ADPLD).

摘要

Mutations in Prkcsh and Sec63, which are involved in protein translocation, folding and quality control pathways in the ER, have been shown to be associated with the occurrence of autosomal dominant polycystic liver disease (ADPLD). ADPLD is characterized by the presence of multiple bile duct-derived cysts. Prkcsh encodes the non-catalytic beta subunit of glucosidase II (GIIbeta), the ER glucose trimming enzyme involved in the calnexin-calreticulin cycle of integral membrane and secreted protein maturation and folding, whereas Sec63 codes for SEC63, which is associated with the Sec61/62 ER translocon. Since these two proteins are not directly linked with the primary cilia which has a well established role in the pathogenesis of polycystic disease, we first set forth to characterize the genetic interaction between the three main ciliary integral membrane cystic protein candidates, polycystin-1 (PC1), polycystin-2 (PC2), and fibrocystin/polyductin (FPC) and either Prkcsh or Sec63 using relevant mouse models. We found polycystin-1 to be the main regulator of the kidney and liver cystic phenotype due to inactivation of either Prkcsh or Sec63 as heterozygosity or overexpression at the Pkd1 locus worsened or rescued the cystic phenotype, respectively. We have also revealed a novel interaction between one of the ADPLD loci ( Sec63) and ARPKD (Pkhd1) as the double mutant mice display a much more severe phenotype than either of the single mutants which implies that Sec63 may be a modulator of both the ADPKD and ARPKD phenotypes in patients.;At the molecular level, we found a correlation between Pkd1 dosage and a pro-proliferative response on both the Prkcsh and Sec63 loss-of-function background. Furthermore, the expression and trafficking of polycystin-1 was reduced in the absence of Prkcsh , further supporting the genetic findings.;Finally we have unveiled a biochemical and genetic interaction between the Ire1-Xbp1 branch of the unfolded protein response (the main transcriptional modulator of UPR) and Sec63 , where the Sec63/Xbp1 knockout animals displayed an exacerbation of the phenotype compared with Sec63 mutants alone suggesting the UPR is playing a protective role in the absence of Sec63.;In conclusion, our findings lend support to the idea of a non-allelic complementation network present among ADPLD-ADPKD-ARPKD-UPR genes.