Hyperosmotic stress stimulates autophagy via polycystin-2

// Daniel Peña-Oyarzun 1,2,* , Rodrigo Troncoso 1,3,* , Catalina Kretschmar 1,4 , Cecilia Hernando 1,4 , Mauricio Budini 4 , Eugenia Morselli 5 , Sergio Lavandero 1,2,6 and Alfredo Criollo 1,4 1 Advanced Center for Chronic Diseases, Facultad Ciencias Quimicas y Farmaceuticas & Facultad Medicina, Universidad de Chile, Santiago, Chile 2 Center for Molecular Studies of the Cell, Facultad de Medicina, Universidad de Chile, Santiago, Chile 3 Instituto de Nutrición y Tecnología de los Alimentos, Universidad de Chile, Santiago, Chile 4 Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile, Santiago, Chile 5 Departamento de Fisiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile 6 Department of Internal Medicine (Cardiology Division), University of Texas Southwestern Medical Center, Dallas, TX, USA * These authors have contributed equally to this work Correspondence to: Alfredo Criollo, email: // Sergio Lavandero, email: // Keywords : hyperosmotic stress, polycystin-2, mTOR, Autophagy Received : May 10, 2017 Accepted : June 21, 2017 Published : July 05, 2017 Abstract Various intracellular mechanisms are activated in response to stress, leading to adaptation or death. Autophagy, an intracellular process that promotes lysosomal degradation of proteins, is an adaptive response to several types of stress. Osmotic stress occurs under both physiological and pathological conditions, provoking mechanical stress and activating various osmoadaptive mechanisms. Polycystin-2 (PC2), a membrane protein of the polycystin family, is a mechanical sensor capable of activating the cell signaling pathways required for cell adaptation and survival. Here we show that hyperosmotic stress provoked by treatment with hyperosmolar concentrations of sorbitol or mannitol induces autophagy in HeLa and HCT116 cell lines. In addition, we show that mTOR and AMPK, two stress sensor proteins involved modulating autophagy, are downregulated and upregulated, respectively, when cells are subjected to hyperosmotic stress. Finally, our findings show that PC2 is required to promote hyperosmotic stress-induced autophagy. Downregulation of PC2 prevents inhibition of hyperosmotic stress-induced mTOR pathway activation. In conclusion, our data provide new insight into the role of PC2 as a mechanosensor that modulates autophagy under hyperosmotic stress conditions.