Protein phosphatase 1? interacts with a novel ciliary targeting sequence of polycystin-1 and regulates polycystin-1 trafficking.

ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder causing renal failure. Mutations of polycystic kidney disease 1 (PKD1) account for most ADPKD cases. Defective ciliary localization of polycystin-1 (PC1), a large integral membrane protein encoded by PKD1, underlies the pathogenesis of a subgroup of patients with ADPKD. However, the mechanisms by which PC1 and other ciliary proteins traffic to the primary cilium remain poorly understood. A ciliary targeting sequence (CTS) that resides in ciliary receptors is considered to function in the process. It has been reported that the VxP motif in the intracellular C-terminal tail of PC1 functions as a CTS in an ADP ribosylation factor 4 (Arf4)/ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (ASAP1)-dependent manner. However, other recent studies have revealed that this motif is dispensable for PC1 trafficking to cilia. In this study, we identified a novel CTS consisting of 8 residues (RHKVRFEG) in the PC1 C tail. We found that this motif is sufficient to bind protein phosphatase 1 (PP1)?, a ubiquitously expressed phosphatase in the phosphoprotein phosphatase (PPP) family. Mutations in this CTS motif disrupt binding with PP1? and impair ciliary localization of PC1. Additionally, short hairpin RNA-mediated knockdown of PP1? results in reduced ciliary localization of PC1 and elongated cilia, suggesting a role for PP1? in the regulation of ciliary structure and function.-Luo, C., Wu, M., Su, X., Yu, F., Brautigan, D. L., Chen, J., Zhou, J. Protein phosphatase 1? interacts with a novel ciliary targeting sequence of polycystin-1 and regulates polycystin-1 trafficking.

SUBMITTER: Luo C 

PROVIDER: S-EPMC6704455 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature