C-31: Coping with water loss: Protecting your proteome under stress

The nematode C. elegans is a powerful model system for defining the cellular and molecular mechanisms by which animal cells cope with water loss. We have demonstrated using genome wide RNAi screening that highly conserved genes required for proteostasis are also critical components of a cellular osmosensing and osmoprotective network. Proteostasis is the maintenance of protein function and is mediated by the tightly integrated activities of gene transcription, RNA metabolism and protein synthesis, folding, assembly, trafficking, disassembly and degradation. Hypertonic stress induced water loss causes widespread and striking protein aggregation and misfolding in C. elegans . Survival in desiccating environments requires the function of gene products that detect and destroy those damaged proteins. Synthesis of new proteins is rapidly inhibited in response to cellular water loss via activation of the GCN-2 kinase signaling cascade and phosphorylation of the translation initiation factor eIF2a. Reduction of translation rate minimizes hypertonic stress induced protein damage. Inhibition of protein synthesis by hypertonic stress, knockdown of genes required for translation, or protein synthesis inhibitors also functions as a signal that activates osmoprotective gene transcription via the WNK and GCK-VI subfamily kinases WNK-1 and GCK-3. WNK and GCK-VI kinases are highly conserved and play central roles in cellular and systemic osmoregulation in humans. Taken together, these findings provide the foundation for ongoing development of an integrated understanding of the genetic, molecular and cellular pathways by which animal cells detect osmotic perturbations and cope with osmotic stress induced cellular and molecular damage.