Ciliary exclusion of Polycystin-2 promotes kidney cystogenesis in an autosomal dominant polycystic kidney disease model

Rebecca V Walker,Jennifer L Keynton,Daniel T Grimes,Martin M Knight,Debbie J Williams,Vrinda Sreekumar,Chris Esapa,Dongsheng Wu,Dominic P Norris

doi:10.1038/s41467-019-12067-y

Abstract

The human PKD2 locus encodes Polycystin-2 (PC2), a TRPP channel that localises to several distinct cellular compartments, including the cilium. PKD2 mutations cause Autosomal Dominant Polycystic Kidney Disease (ADPKD) and affect many cellular pathways. Data underlining the importance of ciliary PC2 localisation in preventing PKD are limited because PC2 function is ablated throughout the cell in existing model systems. Here, we dissect the ciliary role of PC2 by analysing mice carrying a non-ciliary localising, yet channel-functional, PC2 mutation. Mutants develop embryonic renal cysts that appear indistinguishable from mice completely lacking PC2. Despite not entering the cilium in mutant cells, mutant PC2 accumulates at the ciliary base, forming a ring pattern consistent with distal appendage localisation. This suggests a two-step model of ciliary entry; PC2 first traffics to the cilium base before TOP domain dependent entry. Our results suggest that PC2 localisation to the cilium is necessary to prevent PKD.

Highlights

The human PKD2 locus encodes Polycystin-2 (PC2), a transient receptor potential polycystic (TRPP) channel that localises to several distinct cellular compartments, including the cilium
Recent work has argued that the primary cilium is not a calciumresponsive mechanosensor and that calcium signals are not relayed into the cell from the cilium[22], questioning the relationship between PC2 and the primary cilium in Autosomal Dominant Polycystic Kidney Disease (ADPKD)
During the establishment of L-R pattern in the early embryo, PC2 interacts with PKD1L138 and the proteins are argued to function within the cilium in response to fluid flow[36]

Summary

Introduction

The human PKD2 locus encodes Polycystin-2 (PC2), a TRPP channel that localises to several distinct cellular compartments, including the cilium. Despite not entering the cilium in mutant cells, mutant PC2 accumulates at the ciliary base, forming a ring pattern consistent with distal appendage localisation. This suggests a two-step model of ciliary entry; PC2 first traffics to the cilium base before TOP domain dependent entry. Polycystin-2 (PC2) is an integral, multi-pass membrane protein with six transmembrane domains and a characteristic large extracellular loop (S1–S2 loop) It is a member of the transient receptor potential polycystic (TRPP) family of cation channels acting as a non-selective cation channel[1]. Like many other cystic renal diseases, ADPKD involves proteins that reside within or interact with the primary cilium[12]. While a long-established relationship exists between cilia and Polycystins, the importance of ciliary localisation remains to be determined

Methods

Results

Conclusion