Abstract
SKN-1, the Caenorhabditis elegans Nrf1/2/3 ortholog, promotes both oxidative stress resistance and longevity. SKN-1 responds to oxidative stress by upregulating genes that detoxify and defend against free radicals and other reactive molecules, a SKN-1/Nrf function that is both well-known and conserved. Here we show that SKN-1 has a broader and more complex role in maintaining cellular stress defenses. SKN-1 sustains expression and activity of the ubiquitin-proteasome system (UPS) and coordinates specific protective responses to perturbations in protein synthesis or degradation through the UPS. If translation initiation or elongation is impaired, SKN-1 upregulates overlapping sets of cytoprotective genes and increases stress resistance. When proteasome gene expression and activity are blocked, SKN-1 activates multiple classes of proteasome subunit genes in a compensatory response. SKN-1 thereby maintains UPS activity in the intestine in vivo under normal conditions and promotes survival when the proteasome is inhibited. In contrast, when translation elongation is impaired, SKN-1 does not upregulate proteasome genes, and UPS activity is then reduced. This indicates that UPS activity depends upon presence of an intact translation elongation apparatus; and it supports a model, suggested by genetic and biochemical studies in yeast, that protein synthesis and degradation may be coupled processes. SKN-1 therefore has a critical tissue-specific function in increasing proteasome gene expression and UPS activity under normal conditions, as well as when the UPS system is stressed, but mounts distinct responses when protein synthesis is perturbed. The specificity of these SKN-1–mediated stress responses, along with the apparent coordination between UPS and translation elongation activity, may promote protein homeostasis under stress or disease conditions. The data suggest that SKN-1 may increase longevity, not only through its well-documented role in boosting stress resistance, but also through contributing to protein homeostasis.
Highlights
Maintenance of protein homeostasis is critical for organismal health, and protection against environmental challenges
The evolutionarily conserved C. elegans protein SKN-1 promotes stress resistance and longevity, and it defends against toxic small molecules
Proteasome activity depends upon the proper functioning of the protein synthesis apparatus
Summary
Maintenance of protein homeostasis is critical for organismal health, and protection against environmental challenges. Protein homeostasis depends upon the balance among the processes of protein synthesis, folding, and degradation. Disruptions in this balance result in accumulation of abnormal proteins, which over time leads to deterioration of cellular functions, and to cell death [1,2]. The ubiquitin-proteasome system (UPS) regulates the stability of proteins involved in a wide range of cellular processes [6]. The 19S regulatory particle facilitates the entry of polyubiquitinated proteins, and is composed of base and lid subcomplexes [6,7]. It is a major challenge to understand how the levels and activity of the proteasome are regulated to maintain the balance of protein synthesis and degradation
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