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TRIM24 is an insulin-responsive regulator of P-bodies.

Published version
Peer-reviewed

Type

Article

Change log

Authors

Wei, Wen 
Chen, Qiaoli 
Liu, Minjun 
Sheng, Yang 
OuYang, Qian 

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.

Description

Keywords

Animals, Insulin, Mice, Nuclear Proteins, PPAR gamma, Processing Bodies, RNA, Messenger, Transcription Factors, Ubiquitin-Protein Ligases

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

13

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (G0802051)
Medical Research Council (G0400192)
Medical Research Council (MC_UU_12012/2)
Medical Research Council (MC_UU_12012/5)
MRC (MC_UU_00014/2)
Medical Research Council (MC_PC_12012)
British Heart Foundation (RG/18/7/33636)
MRC (MC_UU_00014/5)