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Insulin signaling regulates longevity through protein phosphorylation in Caenorhabditis elegans

Author

Listed:
  • Wen-Jun Li

    (Peking University
    National Institute of Biological Sciences)

  • Chen-Wei Wang

    (Huazhong University of Science and Technology
    Nanjing University Institute of Artificial Intelligence Biomedicine)

  • Li Tao

    (National Institute of Biological Sciences
    Stanford University)

  • Yong-Hong Yan

    (National Institute of Biological Sciences)

  • Mei-Jun Zhang

    (National Institute of Biological Sciences
    Annoroad Gene Tech. Co., Ltd.)

  • Ze-Xian Liu

    (Huazhong University of Science and Technology
    Sun Yat-sen University Cancer Center)

  • Yu-Xin Li

    (National Institute of Biological Sciences
    University of California San Diego)

  • Han-Qing Zhao

    (National Institute of Biological Sciences)

  • Xue-Mei Li

    (Peking University
    National Institute of Biological Sciences)

  • Xian-Dong He

    (National Institute of Biological Sciences)

  • Yu Xue

    (Huazhong University of Science and Technology
    Nanjing University Institute of Artificial Intelligence Biomedicine)

  • Meng-Qiu Dong

    (National Institute of Biological Sciences
    Tsinghua University)

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.

Suggested Citation

  • 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 & Meng-Qiu Dong, 2021. "Insulin signaling regulates longevity through protein phosphorylation in Caenorhabditis elegans," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24816-z
    DOI: 10.1038/s41467-021-24816-z
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    Cited by:

    1. Yan-Ping Zhang & Wen-Hong Zhang & Pan Zhang & Qi Li & Yue Sun & Jia-Wen Wang & Shaobing O. Zhang & Tao Cai & Cheng Zhan & Meng-Qiu Dong, 2022. "Intestine-specific removal of DAF-2 nearly doubles lifespan in Caenorhabditis elegans with little fitness cost," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Gangming Zhang & Chunwei Zheng & Yue-he Ding & Craig Mello, 2024. "Casein kinase II promotes piRNA production through direct phosphorylation of USTC component TOFU-4," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

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