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.
Highlights
Osmotic homeostasis is crucial for maintaining normal cell function
Time-dependent changes in autophagy were assessed in Human cervical cancer cell line (HeLa) and HCT116 cells treated with sorbitol or mannitol
While epithelial cells in the renal tubules or duodenal cells in the intestinal tract are routinely subject to severe osmotic variations under physiological conditions [56, 63], other cell types cannot cope with the osmotic variations that characterize some pathologies [64]
Summary
Osmotic homeostasis is crucial for maintaining normal cell function. Under physiological conditions, renal tubule and gastrointestinal tract cells are routinely subjected to severe changes in osmolarity. In other cell types, hyperosmotic stress may promote various human pathologies. Imbalanced fluid tonicity provokes osmotic stress, which triggers a series of adaptive mechanisms to ensure cell survival. Transporter translocation [8], transcription factor activation [9], osmolyte synthesis [10], upregulation of antioxidant and chaperone proteins [11], cytoskeletal remodeling [12] and cell volume changes [13] are activated rapidly during osmotic stress. Hyperosmotic stress leads to intracellular accumulation of damaged, aggregated, misfolded and oxidized proteins, which can activate cellular degradation mechanisms. Studies have shown that the main cellular protein turnover systems, the autophagy and ubiquitin proteasome pathways, are upregulated under hyperosmotic stress conditions [17, 18]
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