| Title | Insulin signaling regulates longevity through protein phosphorylation in Caenorhabditis elegans |
| 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 |
| Affiliation | Peking Univ, Sch Life Sci, Beijing, Peoples R China Natl Inst Biol Sci, Beijing, Peoples R China Huazhong Univ Sci Arid Technol, Coll Life Sci & Technol, Ctr Artificial Intelligence Biol, Minist Educ,Key Lab Mol Biophys,Hubei Bioinformat, Wuhan, Hubei, Peoples R China Nanjing Univ, Inst Artificial Intelligence Biomed, Nanjing, Jiangsu, Peoples R China Tsinghua Univ, Tsinghua Inst Multidisciplinary Biomed Res, Beijing, Peoples R China Stanford Univ, Dept Biol, Stanford, CA 94305 USA Annoroad Gene Tech Co Ltd, Beijing, Peoples R China Sun Yat Sen Univ Canc Ctr, Collaborat Innovat Ctr Canc Med, State Key Lab Oncol South China, Guangzhou, Peoples R China Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92093 USA |
| Keywords | LIFE-SPAN EXTENSION INHIBIT TRANSLATION GENETICS DAF-16 METABOLISM STABILITY UNIVERSAL ACCURACY MUSCLE GROWTH |
| Issue Date | 27-Jul-2021 |
| Publisher | NATURE COMMUNICATIONS |
| 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-2 alpha 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. |
| URI | http://hdl.handle.net/20.500.11897/623321 |
| ISSN | 2041-1723 |
| DOI | 10.1038/s41467-021-24816-z |
| Indexed | SCI(E) |
| Appears in Collections: | 生命科学学院 |
