In Caenorhabditis elegans, ablation of germline stem cells (GSCs) extends lifespan, but also increases fat accumulation and alters lipid metabolism, raising the intriguing question of how these effects might be related. Here, we show that a lack of GSCs results in a broad transcriptional reprogramming in which the conserved detoxification regulator SKN-1/Nrf increases stress resistance, proteasome activity, and longevity. SKN-1 also activates diverse lipid metabolism genes and reduces fat storage, thereby alleviating the increased fat accumulation caused by GSC absence. Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction. We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids. This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.DOI: http://dx.doi.org/10.7554/eLife.07836.001
SUMMARY Emerging evidence suggests that many proteins may be regulated through cysteine modification, but the extent and functions of this signaling remain largely unclear. The endoplasmic reticulum (ER) transmembrane protein IRE-1 maintains ER homeostasis by initiating the unfolded protein response (UPRER). Here we show in C. elegans and mammalian cells that IRE-1 has a distinct redox-regulated function in cytoplasmic homeostasis. Reactive oxygen species (ROS) that are generated at the ER or by mitochondria sulfenylate a cysteine within the IRE-1 kinase activation loop. This inhibits the IRE-1-mediated UPRER, and initiates the p38/SKN-1(Nrf2) antioxidant response, thereby increasing stress resistance and lifespan. Many AGC-family kinases (AKT, p70S6K, PKC, ROCK1) seem to be regulated similarly. The data reveal that IRE-1 has an ancient function as a cytoplasmic sentinel that activates p38 and SKN-1(Nrf2), and indicate that cysteine modifications induced by ROS signals can direct proteins to adopt unexpected functions, and may coordinate many cellular processes.
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