Insulin signaling regulates longevity through protein phosphorylation in Caenorhabditis elegans

Wen-Jun Li, Chen-Wei Wang, Li Tao, Yong-Hong Yan, Mei-Jun Zhang, Ze-Xian Liu, Yu-Xin Li, Han-Qing Zhao, Xue-Mei Li, Xian-Dong He, Yu Xue () and Meng-Qiu Dong ()
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Wen-Jun Li: Peking University
Chen-Wei Wang: Huazhong University of Science and Technology
Li Tao: National Institute of Biological Sciences
Yong-Hong Yan: National Institute of Biological Sciences
Mei-Jun Zhang: National Institute of Biological Sciences
Ze-Xian Liu: Huazhong University of Science and Technology
Yu-Xin Li: National Institute of Biological Sciences
Han-Qing Zhao: National Institute of Biological Sciences
Xue-Mei Li: Peking University
Xian-Dong He: National Institute of Biological Sciences
Yu Xue: Huazhong University of Science and Technology
Meng-Qiu Dong: National Institute of Biological Sciences

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-24816-z

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