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.
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, School of Medicine, Nanjing University, Nanjing, 210061, China.
Nat Commun. 2022 Jul 8;13(1):3972. doi: 10.1038/s41467-022-31735-0.
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.
胰岛素是一种强有力的 mRNA 转录和翻译诱导剂，有助于代谢调节。胰岛素也被认为通过处理体（P 体）分子机制来调节 mRNA 的稳定性。然而，胰岛素是否以及如何通过 P 体调节 mRNA 的稳定性尚不清楚。在这里，我们表明 E3 连接酶 TRIM24 是将胰岛素信号传递到 P 体的关键因素。在胰岛素刺激下，蛋白激酶 B（PKB，也称为 Akt）磷酸化 TRIM24 并刺激其从核内易位到细胞质中。TRIM24 在细胞质中与 P 体的几个关键成分相互作用，促进它们的多泛素化，从而稳定 Pparγ mRNA。在小鼠中通过 knockin 突变使 TRIM24 E3 连接酶失活或阻止其磷酸化，通过 P 体促进肝 Pparγ 降解。因此，两种 knockin 突变都能缓解高脂肪饮食喂养的小鼠的肝脂肪变性。我们的结果表明 TRIM24 在将胰岛素信号传递到 P 体中起关键作用，并为治疗肝脂肪变性提供了治疗意义。
