{"version":"desci-nodes-0.2.0","components":[{"id":"root","name":"root","type":"data-bucket","payload":{"cid":"bafybeiheufbvcdz3mhc35izlsgsoli7wwm4jz3ra2tpee3ucc3zuma5bme","path":"root"}},{"id":"9186a9b4-49a5-44b8-9001-e781540a672e","name":"Research Report","type":"pdf","subtype":"research-article","payload":{"url":"bafybeidxwz7l2o5rxzhcilfelsuayhbfqd3oa3lbk57hxcgszmmxgsuxai","path":"root/Research Report","title":"A megaprotein brake for aging and insulin-mTOR signaling","ontologyPurl":"","cedarLink":"","controlledVocabTerms":[],"keywords":["Insulin-mTOR Signaling","Aging","LPD-3 Megaprotein","Phospholipid Trafficking","Lipidomic Profiling","Hexaceramide Biosynthesis","HYL-1","INS-7 Insulin","Lifespan Regulation","Alkuraya-Kučinskas Syndrome","C. elegans Model","mTORC2 Component","Sphingolipid-Hexaceramide Pathway","DAF-2 Insulin Receptor","LET-363 mTOR","Antagonistic Pleiotropy","Anabolic Growth"],"description":"Insulin-mTOR signaling drives anabolic growth during organismal development, while its late-life antagonistic pleiotropy affects aging and compromises lifespan across animal phylogeny. 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 over-produced and shortens lifespan in lpd-3 mutants, a C. elegans model of human Alkuraya-Kučinskas syndrome. LPD-3 forms a bridge-like tunnel megaprotein to facilitate phospholipid trafficking to plasma membranes. Lipidomic profiling reveals increased abundance of hexaceramide species in lpd-3 mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1 (Homolog of Yeast Longevity). Reducing HYL-1 activity decreases INS-7 levels and rescues the shortened lifespan of lpd-3 mutants through insulin receptor/DAF-2 and mTOR/LET-363. LPD-3 antagonizes SINH-1, a key mTORC2 component, and decreases expression with age in wild type animals. We propose that LPD-3 acts as a megaprotein brake for aging and its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways."},"starred":true},{"id":"222faed9-65c2-470a-96be-a8121bec117b","name":"Supp Table 1","type":"data","payload":{"cid":"bafkreiamfqiamrgnm5ahcstyocolh5nldkjnwzwup4zylii3eoizqcm3rm","path":"root/Supp Table 1","title":"Supplementary Data","ontologyPurl":"","cedarLink":"","controlledVocabTerms":[],"keywords":["Insulin-mTOR Signaling","Aging","LPD-3 Megaprotein","Phospholipid Trafficking","Lipidomic Profiling","Hexaceramide Biosynthesis","HYL-1","INS-7 Insulin","Lifespan Regulation","Alkuraya-Kučinskas Syndrome","C. elegans Model","mTORC2 Component","Sphingolipid-Hexaceramide Pathway","DAF-2 Insulin Receptor","LET-363 mTOR","Antagonistic Pleiotropy","Anabolic Growth"],"description":"Supplementary Data for \"A megaprotein brake for aging and insulin-mTOR signaling\""},"starred":true}],"authors":[],"title":"A megaprotein brake for aging and insulin-mTOR signaling","defaultLicense":"CC BY","researchFields":["Biology","Molecular biology","Genetics","Cell Biology","Biochemistry","Gerontology","Developmental Biology","Systems Biology"],"dpid":{"prefix":"beta","id":"70"}}