LPD-3 as a megaprotein brake for aging and insulin-mTOR signaling in C. elegans.

Autor:	Pandey T; Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA, USA., Wang B; Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA, USA., Wang C; Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA, USA., Zu J; Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA, USA., Deng H; Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA., Shen K; Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA., do Vale GD; Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA., McDonald JG; Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA., Ma DK; Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA, USA. Electronic address: dengke.ma@ucsf.edu.
Jazyk:	angličtina
Zdroj:	Cell reports [Cell Rep] 2024 Mar 26; Vol. 43 (3), pp. 113899. Date of Electronic Publication: 2024 Mar 05.
DOI:	10.1016/j.celrep.2024.113899
Abstrakt:	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. Competing Interests: Declaration of interests The authors declare no competing interests. (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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