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Ssu72 phosphatase is essential for thermogenic adaptation by regulating cytosolic translation

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  • Eun-Ji Park

    (Sungkyunkwan University School of Medicine)

  • Hyun-Soo Kim

    (Sungkyunkwan University School of Medicine)

  • Do-Hyoung Lee

    (Sungkyunkwan University School of Medicine)

  • Su-Min Kim

    (Sungkyunkwan University School of Medicine)

  • Joon-Sup Yoon

    (Sungkyunkwan University School of Medicine)

  • Ji-Min Lee

    (Soonchunhyang University)

  • Se Jin Im

    (Sungkyunkwan University School of Medicine)

  • Ho Lee

    (Research Institute, National Cancer Center)

  • Min-Woo Lee

    (Soonchunhyang University)

  • Chang-Woo Lee

    (Sungkyunkwan University School of Medicine
    Sungkyunkwan University)

Abstract

Brown adipose tissue (BAT) plays a pivotal role in maintaining body temperature and energy homeostasis. BAT dysfunction is associated with impaired metabolic health. Here, we show that Ssu72 phosphatase is essential for mRNA translation of genes required for thermogenesis in BAT. Ssu72 is found to be highly expressed in BAT among adipose tissue depots, and the expression level of Ssu72 is increased upon acute cold exposure. Mice lacking adipocyte Ssu72 exhibit cold intolerance during acute cold exposure. Mechanistically, Ssu72 deficiency alters cytosolic mRNA translation program through hyperphosphorylation of eIF2α and reduces translation of mitochondrial oxidative phosphorylation (OXPHOS) subunits, resulting in mitochondrial dysfunction and defective thermogenesis in BAT. In addition, metabolic dysfunction in Ssu72-deficient BAT returns to almost normal after restoring Ssu72 expression. In summary, our findings demonstrate that cold-responsive Ssu72 phosphatase is involved in cytosolic translation of key thermogenic effectors via dephosphorylation of eIF2α in brown adipocytes, providing insights into metabolic benefits of Ssu72.

Suggested Citation

  • Eun-Ji Park & Hyun-Soo Kim & Do-Hyoung Lee & Su-Min Kim & Joon-Sup Yoon & Ji-Min Lee & Se Jin Im & Ho Lee & Min-Woo Lee & Chang-Woo Lee, 2023. "Ssu72 phosphatase is essential for thermogenic adaptation by regulating cytosolic translation," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36836-y
    DOI: 10.1038/s41467-023-36836-y
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    References listed on IDEAS

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    1. Kazuhiro Ikeda & Sachiko Shiba & Kuniko Horie-Inoue & Kunitoshi Shimokata & Satoshi Inoue, 2013. "A stabilizing factor for mitochondrial respiratory supercomplex assembly regulates energy metabolism in muscle," Nature Communications, Nature, vol. 4(1), pages 1-9, October.
    2. Miao Wang & Randal J. Kaufman, 2016. "Protein misfolding in the endoplasmic reticulum as a conduit to human disease," Nature, Nature, vol. 529(7586), pages 326-335, January.
    3. Mary T. Couvillion & Iliana C. Soto & Gergana Shipkovenska & L. Stirling Churchman, 2016. "Synchronized mitochondrial and cytosolic translation programs," Nature, Nature, vol. 533(7604), pages 499-503, May.
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