Fig. 1. Hypertonic stress response pathways in C. elegans. The induction of osmotically regulated genes, such as gpdh-1, during hypertonic stress (HTS) is regulated through both transcriptional (blue) and post-transcriptional (red) mechanisms. At least three pathways regulate the transcriptional induction of gpdh-1. First, inhibition of proteins that maintain protein folding and new protein synthesis activate gpdh-1 expression. HTS-induced decreases in protein translation lead to increased gpdh-1 transcription through a gcn-1/2 and wnk-1/gck-3 dependent pathway. Additionally, while significant work shows that HTS causes unique types of protein damage and inhibition of protein homeostasis genes activates the HTSR, the specific signaling mechanisms linking HTS-induced protein damage to gpdh-1 mRNA upregulation are not known. Second, the HTSR transcriptional response is negatively regulated by extracellular proteins that function upstream of the transmembrane protein PTR-23/patched-related protein 23, and the GATA erythroid-like transcription factors ELT-2 and ELT-3. However, ptr-23 is not required for all osmotically regulated gene expression and as such at least one ptr-23 independent pathway must exist. It is unknown if this ptr-23 independent pathway functions through the GATA transcription factors. It also remains unknown if HTS itself can activate ELT-2/-3 through an extracellular protein and PTR-23 independent pathway. Finally, the O-GlcNAc transferase OGT-1 regulates GPDH-1 protein translation through a post-transcriptional pathway. ogt-1 is required for osm-8 and osm-11 phenotypes, suggesting there is some crosstalk between the extracellular protein transcriptional pathway and the ogt-1 post-transcriptional pathway. The precise mechanism by which ogt-1 induces GPDH-1 protein expression is unknown, but it could include regulation of mRNA cleavage, 3' UTR usage, mRNA export, initiation factor interactions or ribosomal elongation. The output of both the transcriptional and post-transcriptional pathways are two-fold. First, they mediate acclimation that enable animals to survive and reproduce in hypertonic environments. Second, these pathways may also modulate the function of osmosensory neurons such that once acclimation has occurred, behavioral avoidance to hypertonic stimuli is no longer necessary.