Specific SKN-1Stress Responses And Screening Of New Genes Involved In Autophagy In Caenorhabditis Elegans

SKN-1, the C. elegans Nrf1/2/3ortholog, promotes both oxidative stress resistanceand longevity. SKN-1responds to oxidative stress by upregulating genes that detoxify anddefend against free radicals and other reactive molecules, a SKN-1/Nrf function that isboth well-known and conserved. Here we show that SKN-1has a broader and morecomplex role in maintaining cellular stress defenses. SKN-1sustains expression andactivity of the ubiquitin-proteasome system (UPS), and coordinates specific protectiveresponses to perturbations in protein synthesis or degradation through the UPS. Iftranslation initiation or elongation is impaired, SKN-1upregulates overlapping sets ofcytoprotective genes and increases stress resistance. When proteasome gene expressionand activity are blocked, SKN-1activates multiple classes of proteasome subunit genes ina compensatory response. SKN-1thereby maintains UPS activity in the intestine in vivounder normal conditions, and promotes survival when the proteasome is inhibited. Incontrast, when translation elongation is impaired SKN-1does not upregulate proteasomegenes, and UPS activity is then reduced. This indicates that UPS activity depends uponpresence of an intact translation elongation apparatus, and supports a model suggested bygenetic and biochemical studies in yeast, that protein synthesis and degradation may becoupled processes. SKN-1therefore has a critical tissue-specific function in increasingproteasome gene expression and UPS activity under normal conditions, as well as whenthe UPS system is stressed, but mounts distinct responses when protein synthesis isperturbed. The specificity of these SKN-1-mediated stress responses, along with theapparent coordination between UPS and translation elongation activity, may promoteprotein homeostasis under stress or disease conditions. The data suggest that SKN-1mayincrease longevity not only through its well-documented role in boosting stress resistance,but also through contributing to protein homeostasis.Degradation processes are an important aspect of protein quality control systems ineukaryotic cells. The two major protein degradation pathways in eukaryotes are theubiquitin-proteasome system and autophagy. Autophagy is thought to promote both celland organism survival by providing fundamental building blocks to maintain energy homeostasis during starvation. Here our data based on an RNAi screening identify45genes, including33possible positive regulators and12possible negative regulators, mightbe involved in the regulation of autophagy in C. elegans.