Insulin signaling regulates longevity through protein phosphorylation in Caenorhabditis elegans

• Published in: Nature communications Vol. 12; no. 1; pp. 4568 - 16
• Main Authors: Li, Wen-Jun, Wang, Chen-Wei, Tao, Li, Yan, Yong-Hong, Zhang, Mei-Jun, Liu, Ze-Xian, Li, Yu-Xin, Zhao, Han-Qing, Li, Xue-Mei, He, Xian-Dong, Xue, Yu, Dong, Meng-Qiu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.07.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/89; 14/63; 38/70; 631/114/1305; 631/136/7; 631/1647/2067; 631/337/458/1733; 64; 64/11; 82/1; 82/58; 96/35; AKT protein; AKT1 protein; Algorithms; Amino Acid Sequence; Animals; Caenorhabditis elegans; Caenorhabditis elegans - physiology; Caenorhabditis elegans Proteins - chemistry; Caenorhabditis elegans Proteins - metabolism; Casein; Casein kinase II; Forkhead protein; Germ Cells - metabolism; Humanities and Social Sciences; Humans; Insulin; Insulin - metabolism; Insulin-like growth factor I; Insulin-Like Growth Factor I - metabolism; Kinases; Learning algorithms; Life span; Longevity; Longevity - physiology; Machine learning; Models, Biological; multidisciplinary; Mutants; Mutation - genetics; Nematodes; Phosphoproteins - metabolism; Phosphorylation; Protein biosynthesis; Protein synthesis; Proteins; Proteome - metabolism; Proteomics; Science; Science (multidisciplinary); Signal Transduction; Signaling; Substrates
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-24816-z

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.