The C. elegans Hypertonic Stress Response: Big Insights from Shrinking Worms

Cell volume is one of the most aggressively defended physiological set points in biology. Changes in intracellular ion and water concentrations, which are induced by changes in metabolism or environmental exposures, disrupt protein folding, enzymatic activity, and macromolecular assemblies. To counter these challenges, cells and organisms have evolved multifaceted, evolutionarily conserved molecular mechanisms to restore cell volume and repair stress induced damage. However, many unanswered questions remain regarding the nature of cell volume 'sensing' as well as the molecular signaling pathways involved in activating physiological response mechanisms. Unbiased genetic screening in the model organism C. elegans is providing new and unexpected insights into these questions, particularly questions relating to the hypertonic stress response (HTSR) pathway. One surprising characteristic of the HTSR pathway in C. elegans is that it is under strong negative regulation by proteins involved in protein homeostasis and the extracellular matrix (ECM). The role of the ECM in particular highlights the importance of studying the HTSR in the context of a live organism where native ECM-tissue associations are preserved. A second novel and recently discovered characteristic is that the HTSR is regulated at the post-transcriptional level. The goal of this review is to describe these discoveries, to provide context for their implications, and to raise outstanding questions to guide future research.