Polycystin 2 is increased in disease to protect against stress-induced cell death

Allison L Brill,Barbara E Ehrlich,Jennifer M Walters,Stuart G Campbell,Jeanne M Nerbonne,Lloyd G Cantley,Marie E Robert,Gilbert Moeckel,Tom T Fischer,Eric K Johnson,Hee Jung Chung,Parker C Wilson,Arnaud Marlier,Lorenzo R Sewanan

doi:10.1038/s41598-019-57286-x

Abstract

Polycystin 2 (PC2 or TRPP1, formerly TRPP2) is a calcium-permeant Transient Receptor Potential (TRP) cation channel expressed primarily on the endoplasmic reticulum (ER) membrane and primary cilia of all cell and tissue types. Despite its ubiquitous expression throughout the body, studies of PC2 have focused primarily on its role in the kidney, as mutations in PC2 lead to the development of autosomal dominant polycystic kidney disease (ADPKD), a debilitating condition for which there is no cure. However, the endogenous role that PC2 plays in the regulation of general cellular homeostasis remains unclear. In this study, we measure how PC2 expression changes in different pathological states, determine that its abundance is increased under conditions of cellular stress in multiple tissues including human disease, and conclude that PC2-deficient cells have increased susceptibility to cell death induced by stress. Our results offer new insight into the normal function of PC2 as a ubiquitous stress-sensitive protein whose expression is up-regulated in response to cell stress to protect against pathological cell death in multiple diseases.

Highlights

Polycystin 2 (PC2 or TRPP1, formerly TRPP2) is a calcium-permeant Transient Receptor Potential (TRP) cation channel expressed primarily on the endoplasmic reticulum (ER) membrane and primary cilia of all cell and tissue types
Because kidney tubules afflicted with ischemia-induced acute kidney injury (AKI) exhibit intracellular Ca2+ overload and altered Ca2+ dynamics[42], we tested whether the expression level of PC2 was changed in AKI-afflicted kidneys
We found that the kidneys afflicted with AKI had significantly higher levels of Pkd[2] mRNA (Fig. 1D), indicating that both PC2 transcript and protein are increased with stress

Summary

Introduction

Polycystin 2 (PC2 or TRPP1, formerly TRPP2) is a calcium-permeant Transient Receptor Potential (TRP) cation channel expressed primarily on the endoplasmic reticulum (ER) membrane and primary cilia of all cell and tissue types. We measure how PC2 expression changes in different pathological states, determine that its abundance is increased under conditions of cellular stress in multiple tissues including human disease, and conclude that PC2-deficient cells have increased susceptibility to cell death induced by stress. Our results offer new insight into the normal function of PC2 as a ubiquitous stress-sensitive protein whose expression is up-regulated in response to cell stress to protect against pathological cell death in multiple diseases. Oxidative and ER stress responses require Ca2+ influx from both the extracellular www.nature.com/scientificreports environment and intracellular stores as a key initial step for combating cell damage[19,20,21,22] This elevated intracellular Ca2+ coordinates many physiological functions, such as changes in Ca2+-dependent gene transcription and activation of pro-survival pathways[23]. Our results indicate that PC2 acts in all tissues as a ubiquitous stress response protein whose expression levels correlate with cell survival in response to stress

Methods

Results

Conclusion