TRIM24 is an insulin-responsive regulator of P-bodies

  • Nat Commun. 2022 Jul 8;13(1):3972. doi: 10.1038/s41467-022-31735-0.
Wen Wei   #  1  2  3 ,  Qiaoli Chen   #  1  2  3 ,  Minjun Liu   #  1  2  3 ,  Yang Sheng   #  1  2  3 ,  Qian OuYang  1  2 ,  Weikuan Feng  1  2 ,  Xinyu Yang  1  2 ,  Longfei Ding  1  2 ,  Shu Su  1  2 ,  Jingzi Zhang  4 ,  Lei Fang  4 ,  Antonio Vidal-Puig  5  6 ,  Hong-Yu Wang  7  8  9 ,  Shuai Chen  10  11  12
Affiliations
  • 1. State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing, 210061, China.
  • 2. MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China.
  • 3. Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China.
  • 4. School of Medicine, Nanjing University, Nanjing, 210061, China.
  • 5. TVP Lab, WT/MRC Institute of Metabolic Science, MRC Metabolic Diseases Unit - Metabolic Research Laboratories, University of Cambridge, Cambridge, UK.
  • 6. Cambridge University Nanjing Centre of Technology and Innovation, Jiangbei Area, Nanjing, China.
  • 7. State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing, 210061, China. [email protected].
  • 8. MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. [email protected].
  • 9. Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. [email protected].
  • 10. State Key Laboratory of Pharmaceutical Biotechnology, Department of Endocrinology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing, 210061, China. [email protected].
  • 11. MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. [email protected].
  • 12. Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. [email protected].
  • # Contributed equally.
PMID: 35803934 DOI: 10.1038/s41467-022-31735-0
Abstract

Insulin is a potent inducer of mRNA transcription and translation, contributing to metabolic regulation. Insulin has also been suggested to regulate mRNA stability through the processing body (P-body) molecular machinery. However, whether and how Insulin regulates mRNA stability via P-bodies is not clear. Here we show that the E3-ligase TRIM24 is a critical factor linking Insulin signalling to P-bodies. Upon Insulin stimulation, protein kinase B (PKB, also known as Akt) phosphorylates TRIM24 and stimulates its shuttling from the nucleus into the cytoplasm. TRIM24 interacts with several critical components of P-bodies in the cytoplasm, promoting their polyubiquitylation, which consequently stabilises PPARγ mRNA. Inactivation of TRIM24 E3-ligase activity or prevention of its phosphorylation via knockin mutations in mice promotes hepatic PPARγ degradation via P-bodies. Consequently, both knockin mutations alleviate hepatosteatosis in mice fed on a high-fat diet. Our results demonstrate the critical role of TRIM24 in linking Insulin signalling to P-bodies and have therapeutic implications for the treatment of hepatosteatosis.

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