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

Taruna Pandey; Bingying Wang; Changnan Wang; Jenny Zu; Huichao Deng; Kang Shen; Goncalo Dias do Vale; Jeffrey G. McDonald; Dengke K. Ma

Cell Reports (Mar 2024)

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

Taruna Pandey,
Bingying Wang,
Changnan Wang,
Jenny Zu,
Huichao Deng,
Kang Shen,
Goncalo Dias do Vale,
Jeffrey G. McDonald,
Dengke K. Ma

Affiliations

Taruna Pandey: Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA, USA
Bingying Wang: Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA, USA
Changnan Wang: Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA, USA
Jenny Zu: Cardiovascular Research Institute and Department of Physiology, University of California San Francisco, San Francisco, CA, USA
Huichao Deng: Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
Kang Shen: Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
Goncalo Dias do Vale: Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
Jeffrey G. McDonald: Center for Human Nutrition and Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
Dengke K. Ma: 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; Corresponding author

Journal volume & issue: Vol. 43, no. 3
p. 113899

Abstract

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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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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