PI3K/AKT/mTOR通路
胰岛素
胰岛素受体
秀丽隐杆线虫
细胞生物学
信号转导
生物
内分泌学
胰岛素抵抗
遗传学
基因
作者
Taruna Pandey,Bingying Wang,Changnan Wang,Jenny Zu,Huichao Deng,Kang Shen,Gonçalo Vale,Jeffrey G. McDonald,K. Dengke
出处
期刊:Cell Reports
[Elsevier]
日期:2024-03-01
卷期号:43 (3): 113899-113899
被引量:1
标识
DOI:10.1016/j.celrep.2024.113899
摘要
Summary
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.
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