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ZFYVE28 mediates insulin resistance by promoting phosphorylated insulin receptor degradation via increasing late endosomes production

Author

Listed:
  • Liang Yu

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Mengchen Xu

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Yupeng Yan

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Shuchen Huang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Mengmeng Yuan

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Bing Cui

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Cheng Lv

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Yu Zhang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Hongrui Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Xiaolei Jin

    (Chinese Academy of Medical Sciences & Peking Union Medical College)

  • Rutai Hui

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Yibo Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

Abstract

Insulin resistance is associated with many pathological conditions, and an in-depth understanding of the mechanisms involved is necessary to improve insulin sensitivity. Here, we show that ZFYVE28 expression is decreased in insulin-sensitive obese individuals but increased in insulin-resistant individuals. Insulin signaling inhibits ZFYVE28 expression by inhibiting NOTCH1 via the RAS/ERK pathway, whereas ZFYVE28 expression is elevated due to impaired insulin signaling in insulin resistance. While Zfyve28 overexpression impairs insulin sensitivity and causes lipid accumulation, Zfyve28 knockout in mice can significantly improve insulin sensitivity and other indicators associated with insulin resistance. Mechanistically, ZFYVE28 colocalizes with early endosomes via the FYVE domain, which inhibits the generation of recycling endosomes but promotes the conversion of early to late endosomes, ultimately promoting phosphorylated insulin receptor degradation. This effect disappears with deletion of the FYVE domain. Overall, in this study, we reveal that ZFYVE28 is involved in insulin resistance by promoting phosphorylated insulin receptor degradation, and ZFYVE28 may be a potential therapeutic target to improve insulin sensitivity.

Suggested Citation

  • Liang Yu & Mengchen Xu & Yupeng Yan & Shuchen Huang & Mengmeng Yuan & Bing Cui & Cheng Lv & Yu Zhang & Hongrui Wang & Xiaolei Jin & Rutai Hui & Yibo Wang, 2023. "ZFYVE28 mediates insulin resistance by promoting phosphorylated insulin receptor degradation via increasing late endosomes production," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-42657-w
    DOI: 10.1038/s41467-023-42657-w
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    References listed on IDEAS

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    1. Daniel D. Shaye & Iva Greenwald, 2002. "Endocytosis-mediated downregulation of LIN-12/Notch upon Ras activation in Caenorhabditis elegans," Nature, Nature, vol. 420(6916), pages 686-690, December.
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