TRIM24 is an insulin-responsive regulator of P-bodies.
TRIM24 is an insulin-responsive regulator of P-bodies.
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DOI：
10.1038/s41467-022-31735-0
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发表时间：
2022-07-08
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
胰岛素是mRNA转录和翻译的有效诱导剂，有助于代谢调节。胰岛素也被认为通过加工体（P体）分子机制调节mRNA稳定性。然而，胰岛素是否以及如何通过P体调节mRNA稳定性尚不清楚。在这里，我们表明，E3连接酶TRIM24是一个关键因素连接胰岛素信号的P体。在胰岛素刺激后，蛋白激酶B（PKB，也称为Akt）磷酸化TRIM 24并刺激其从细胞核穿梭进入细胞质。TRIM24与细胞质中P体的几种关键组分相互作用，促进它们的聚泛素化，从而稳定Pparγ mRNA。小鼠中TRIM 24 E3连接酶活性失活或通过敲入突变防止其磷酸化可促进肝脏Pparγ通过P体降解。因此，两种敲入突变都能减轻高脂饮食喂养的小鼠的脂肪肝。我们的研究结果证明了TRIM24在连接胰岛素信号传导到P体中的关键作用，并对脂肪肝的治疗具有治疗意义。胰岛素促进肝脏脂肪生成，但其潜在的调控机制尚不清楚。在此，作者表明胰岛素将TRIM 24从细胞核转位到胞质P体中以稳定肝脏Pparγ mRNA，并且TRIM 24的失活促进Pparγ降解并加重脂肪肝。
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. 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 Pparγ mRNA, and that inactivation of TRIM24 promotes Pparγ degradation and alleviates hepatosteatosis.
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DOI：
10.1038/nri2413
发表时间：
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期刊：
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影响因子：
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DOI：
10.1073/pnas.1600581113
发表时间：
2016-06-28
影响因子：
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通讯作者：
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