Protein phosphatase 1α 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)α, a ubiquitously expressed phosphatase in the phosphoprotein phosphatase (PPP) family. Mutations in this CTS motif disrupt binding with PP1α and impair ciliary localization of PC1. Additionally, short hairpin RNA-mediated knockdown of PP1α results in reduced ciliary localization of PC1 and elongated cilia, suggesting a role for PP1α 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 1α interacts with a novel ciliary targeting sequence of polycystin-1 and regulates polycystin-1 trafficking.

• Authors: Chong Luo, Maoqing Wu, Xuefeng Su, Fangyan Yu, David L Brautigan, Jianghua Chen, Jing Zhou
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 33 Issue 9 Pg. 9945-9958 (09 2019) ISSN: 1530-6860 [Electronic] United States
• PMID: 31157564 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• TRPP Cation Channels
• polycystic kidney disease 1 protein
• Protein Phosphatase 1
• Alanine

Topics

• Alanine
• Amino Acid Sequence
• Animals
• Cell Line
• Mice
• Mice, Knockout
• Mutagenesis
• Protein Phosphatase 1 (genetics, metabolism)
• Protein Transport
• TRPP Cation Channels (genetics, metabolism)