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
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.
