Ssu72 phosphatase is essential for thermogenic adaptation by regulating cytosolic translation

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 () and Chang-Woo Lee ()
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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

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36836-y

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