Hyperosmotic stress stimulates autophagy via polycystin-2

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.

Safety assessment of the innovative functional food ingredient from Cannabis sativa L. wastes

“…The NFE2L2 pathway may have been activated in response to autophagy that may have been caused by increased osmolarity in culture medium. It was previously reported that various concentrations of sorbitol and mannitol caused hyperosmotic stress and autophagy in human colon cancer cell line HCT116 (26). That mechanism may have promoted expression of NFE2L2 gene in Caco-2 cells in our case.…”

Kinetics of osmotic stress regulates a cell fate switch of cell survival

“…The 'growth/survival & inflammation' group contain proteins that counteract apoptotic responses or indicate growth, proliferation, and inflammatory stimulation. The group contains phosphorylated forms of Bad 45 , Bcl2 46 , two proapoptotic proteins, mTOR 47 , a key node in the cell growth pathway, ribosomal protein S6 48 , a marker for active translation, and p-ZAP70 49,50 , a marker for activated inflammatory signaling.…”

Hyperosmotic Stress Initiates AMPK-Independent Autophagy and AMPK- and Autophagy-Independent Depletion of Thioredoxin 1 and Glyoxalase 2 in HT22 Nerve Cells

“…Recent reports highlighted that downstream of AMPK activation and mTOR inhibition, hyperosmotic stress triggers autophagy [11, 13, 17]. Thus, autophagic markers were evaluated.…”

“…Autophagy and microtubule remodeling have been proposed to play a prominent role in the osmoprotective cell response [12]. In this regard, mechanical sensors are important elements in activating the cell signaling pathways required for cell adaptation and survival [13]. Nevertheless, uncontrolled hyperosmotic stress can lead to apoptotic cell death [10].…”