TRIM24 is an insulin-responsive regulator of P-bodies

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 Ppar gamma mRNA. Inactivation of TRIM24 E3-ligase activity or prevention of its phosphorylation via knockin mutations in mice promotes hepatic Ppar gamma 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. Insulin promotes hepatic lipogenesis, though underlying regulation remains unclear. Here the authors show that insulin translocates TRIM24 from the nucleus into cytosolic P-bodies to stabilise hepatic Ppar gamma mRNA, and that inactivation of TRIM24 promotes Ppar gamma degradation and alleviates hepatosteatosis.

Automated summary

The E3-ligase TRIM24 plays a critical role in linking insulin signalling to the P-body molecular machinery. Insulin stimulation triggers the phosphorylation of TRIM24 by protein kinase B, leading to its translocation from the nucleus to the cytoplasm. In the cytoplasm, TRIM24 interacts with P-body components and promotes their polyubiquitylation, facilitating the stabilization of Ppar gamma mRNA. Inactivation of TRIM24 or prevention of its phosphorylation promotes Ppar gamma degradation via P-bodies, alleviating hepatosteatosis in mice fed on a high-fat diet.