Authors: Wen Wei, Qiaoli Chen, Minjun Liu, Yang Sheng, Qian OuYang, Weikuan Feng, Xinyu Yang, Longfei Ding, Shu Su, Jingzi Zhang, Lei Fang, Antonio Vidal-Puig, Hong-Yu Wang, Shuai Chen
Published: 2022-07-08
DOI: 10.1038/s41467-022-31735-0
Source: Full article
AbstractInsulin 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 PparĪ³ mRNA. Inactivation of TRIM24 E3-ligase activity or prevention of its phosphorylation via knockin mutations in mice promotes hepatic PparĪ³ 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.