PDF(Pubmed)
Abstract：
Insulin-mechanistic target of rapamycin (mTOR) signaling drives anabolic growth during organismal development; its late-life dysregulation contributes to aging and limits lifespans. Age-related regulatory mechanisms and functional consequences of insulin-mTOR remain incompletely understood. Here, we identify LPD-3 as a megaprotein that orchestrates the tempo of insulin-mTOR signaling during C. elegans aging. We find that an agonist insulin, INS-7, is drastically overproduced from early life and shortens lifespan in lpd-3 mutants. LPD-3 forms a bridge-like tunnel megaprotein to facilitate non-vesicular cellular lipid trafficking. Lipidomic profiling reveals increased hexaceramide species in lpd-3 mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1. Reducing the abundance of HYL-1, insulin receptor/DAF-2 or mTOR/LET-363, normalizes INS-7 levels and rescues the lifespan of lpd-3 mutants. LPD-3 antagonizes SINH-1, a key mTORC2 component, and decreases expression with age. We propose that LPD-3 acts as a megaprotein brake for organismal aging and that its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways.
摘要：
雷帕霉素的胰岛素机制靶标（mTOR）信号在机体发育过程中驱动合成代谢生长；其晚年失调导致衰老并限制寿命。胰岛素mTOR的年龄相关调节机制和功能后果仍未完全了解。这里,我们将LPD-3鉴定为在秀丽隐杆线虫衰老过程中协调胰岛素-mTOR信号传导节奏的大蛋白。我们发现激动剂胰岛素，INS-7在lpd-3突变体中从早期生命中急剧过量产生并缩短寿命。LPD-3形成桥状隧道巨蛋白以促进非囊泡细胞脂质运输。脂质组学分析揭示了lpd-3突变体中六妥酰胺物种的增加，伴随着六酰胺生物合成酶的上调，包括HYL-1。降低HYL-1，胰岛素受体/DAF-2或mTOR/LET-363的丰度，使INS-7水平正常化并挽救lpd-3突变体的寿命。LPD-3拮抗SINH-1，一种关键的mTORC2成分，并随着年龄的增长而减少表达。我们建议LPD-3充当生物体衰老的大蛋白制动，其年龄依赖性下降通过鞘脂-六妥酰胺和胰岛素-mTOR途径限制了寿命。
