The ability to sense and respond to proteotoxic insults declines with age, leaving cells vulnerable to chronic and acute stressors. Reproductive cues modulate this decline in cellular proteostasis to influence organismal stress resilience in Caenorhabditis elegans. We previously uncovered a pathway that links the integrity of developing embryos to somatic health in reproductive adults. Here, we show that the nuclear receptor NHR-49, an ortholog of mammalian peroxisome proliferator-activated receptor α (PPARα), regulates stress resilience and proteostasis downstream from embryo integrity and other pathways that influence lipid homeostasis and upstream of HSF-1. Disruption of the vitelline layer of the embryo envelope, which activates a proteostasis-enhancing intertissue pathway in somatic cells, triggers changes in lipid catabolism gene expression that are accompanied by an increase in fat stores. NHR-49, together with its coactivator, MDT-15, contributes to this remodeling of lipid metabolism and is also important for the elevated stress resilience mediated by inhibition of the embryonic vitelline layer. Our findings indicate that NHR-49 also contributes to stress resilience in other pathways known to change lipid homeostasis, including reduced insulin-like signaling and fasting, and that increased NHR-49 activity is sufficient to improve proteostasis and stress resilience in an HSF-1-dependent manner. Together, our results establish NHR-49 as a key regulator that links lipid homeostasis and cellular resilience to proteotoxic stress.

中文翻译：

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通过 NHR-49/MDT-15 的核受体信号传导调节应激恢复力和蛋白质稳态，以响应生殖和代谢线索


感知和响应蛋白毒性损伤的能力随着年龄的增长而下降，使细胞容易受到慢性和急性应激源的影响。生殖线索调节细胞蛋白质稳态的这种下降，从而影响秀丽隐杆线虫的生物体应激恢复力。我们之前发现了一条将发育中的胚胎的完整性与生殖成人的体细胞健康联系起来的途径。在这里，我们表明核受体 NHR-49 是哺乳动物过氧化物酶体增殖物激活受体 α （PPARα） 的直系同源物，调节胚胎完整性下游的应激弹性和蛋白质稳态以及影响脂质稳态和 HSF-1 上游的其他途径。胚胎包膜的卵黄层破坏激活体细胞中增强蛋白质稳态的组织间通路，触发脂质分解代谢基因表达的变化，并伴有脂肪储存的增加。NHR-49 与其共激活因子 MDT-15 一起有助于脂质代谢的这种重塑，并且对于通过抑制胚胎卵黄素层介导的升高的应激恢复力也很重要。我们的研究结果表明，NHR-49 还有助于其他已知改变脂质稳态的途径的应激恢复力，包括减少胰岛素样信号传导和禁食，并且增加的 NHR-49 活性足以以 HSF-1 依赖性方式改善蛋白平衡和应激恢复力。总之，我们的结果将 NHR-49 确立为将脂质稳态和细胞对蛋白毒性应激的恢复力联系起来的关键调节因子。