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Insulin signaling regulates longevity through protein phosphorylation in Caenorhabditis elegans
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Insulin signaling regulates longevity through protein phosphorylation in Caenorhabditis elegans
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Journal Article
Insulin signaling regulates longevity through protein phosphorylation in Caenorhabditis elegans
2021
Overview
Insulin/IGF-1 Signaling (IIS) is known to constrain longevity by inhibiting the transcription factor FOXO. How phosphorylation mediated by IIS kinases regulates lifespan beyond FOXO remains unclear. Here, we profile IIS-dependent phosphorylation changes in a large-scale quantitative phosphoproteomic analysis of wild-type and three IIS mutant
Caenorhabditis elegans
strains. We quantify more than 15,000 phosphosites and find that 476 of these are differentially phosphorylated in the long-lived
daf-2/insulin receptor
mutant. We develop a machine learning-based method to prioritize 25 potential lifespan-related phosphosites. We perform validations to show that AKT-1 pT492 inhibits DAF-16/FOXO and compensates the loss of
daf-2
function, that EIF-2α pS49 potently inhibits protein synthesis and
daf-2
longevity, and that reduced phosphorylation of multiple germline proteins apparently transmits reduced DAF-2 signaling to the soma. In addition, an analysis of kinases with enriched substrates detects that casein kinase 2 (CK2) subunits negatively regulate lifespan. Our study reveals detailed functional insights into longevity.
How phosphorylation mediated by Insulin/IGF-1 Signaling kinases regulates lifespan remains unclear. Here the authors perform a large-scale quantitative phosphoproteomic analysis of wildtype and IIS mutant C. elegans strains to reveal detailed functional insights into longevity.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 14/63
/ 38/70
/ 64
/ 64/11
/ 82/1
/ 82/58
/ 96/35
/ Animals
/ Caenorhabditis elegans - physiology
/ Caenorhabditis elegans Proteins - chemistry
/ Caenorhabditis elegans Proteins - metabolism
/ Casein
/ Humanities and Social Sciences
/ Humans
/ Insulin
/ Insulin-like growth factor I
/ Insulin-Like Growth Factor I - metabolism
/ Kinases
/ Mutants
/ Phosphoproteins - metabolism
/ Proteins
/ Science
