2. Academic Validation
  3. TRIM24 is an insulin-responsive regulator of P-bodies

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

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. wanghy@nicemice.cn.
  • 8 MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. wanghy@nicemice.cn.
  • 9 Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. wanghy@nicemice.cn.
  • 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. schen6@163.com.
  • 11 MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. schen6@163.com.
  • 12 Jiangsu Key Laboratory of Molecular Medicine, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China. schen6@163.com.
  • # 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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