小柯机器人

PCK1磷酸化INSIG1/2促进脂肪形成
2020-04-10 13:30

浙江大学医学院吕志民团队与合作者取得一项新突破。他们发现在脂肪生成过程中糖异生酶磷酸烯醇丙酮酸羧激酶1PCK1)磷酸化INSIG1/2。这一研究成果于202048日发表在《自然》杂志上。

他们显示在人类肝细胞癌(HCC)细胞中激活的AKT,磷酸化胞浆PCK1dSer90位点,PCK1是糖异生中的限速酶。磷酸化的PCK1转移到内质网,在这里它使用GTP作为磷酸盐供体来磷酸化INSIG1Ser207INSIG2Ser151

这种磷酸化作用减少了固醇与INSIG1INSIG2的结合,并破坏了INSIG蛋白与SCAP之间的相互作用,从而导致SREBP裂解激活蛋白(SCAP–SREBP复合物向高尔基体转移,固醇调节元件结合蛋白(SREBPs)蛋白(SREBP1SREBP2)的活化以及下游脂肪形成相关基因的转录,肿瘤细胞增殖和小鼠肿瘤发生。

此外,PCK1Ser90INSIG1Ser207INSIG2Ser151的磷酸化不仅与HCC患者样品中SREBP1的核正相关,而且与不良的HCC预后相关。他们的发现突出了PCK1的蛋白激酶活性在SREBPs激活、脂肪形成和HCC发生中的重要性。

据介绍,癌细胞增殖会增加脂肪生成,而SREBPs的激活在此过程中起着核心作用。SREBP被内质网中的INSIG蛋白、SCAP和固醇组成的复合物抑制。固醇水平对INSIG蛋白和SCAP之间相互作用的调节,对于SCAP-SREBP复合物与内质网的分离和SREBPs的活化至关重要。但是,这种蛋白质的相互作用是否受固醇含量以外的其他机制调节,尤其是致癌信号是否起作用,尚不清楚。

附:英文原文

Title: The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis

Author: Daqian Xu, Zheng Wang, Yan Xia, Fei Shao, Weiya Xia, Yongkun Wei, Xinjian Li, Xu Qian, Jong-Ho Lee, Linyong Du, Yanhua Zheng, Guishuai Lv, Jia-shiun Leu, Hongyang Wang, Dongming Xing, Tingbo Liang, Mien-Chie Hung, Zhimin Lu

Issue&Volume: 2020-04-08

Abstract: Cancer cells increase lipogenesis for their proliferation and the activation of sterol regulatory element-binding proteins (SREBPs) has a central role in this process. SREBPs are inhibited by a complex composed of INSIG proteins, SREBP cleavage-activating protein (SCAP) and sterols in the endoplasmic reticulum. Regulation of the interaction between INSIG proteins and SCAP by sterol levels is critical for the dissociation of the SCAP–SREBP complex from the endoplasmic reticulum and the activation of SREBPs1,2. However, whether this protein interaction is regulated by a mechanism other than the abundance of sterol—and in particular, whether oncogenic signalling has a role—is unclear. Here we show that activated AKT in human hepatocellular carcinoma (HCC) cells phosphorylates cytosolic phosphoenolpyruvate carboxykinase 1 (PCK1), the rate-limiting enzyme in gluconeogenesis, at Ser90. Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP–SREBP complex to the Golgi apparatus, the activation of SREBP proteins (SREBP1 or SREBP2) and the transcription of downstream lipogenesis-related genes, proliferation of tumour cells, and tumorigenesis in mice. In addition, phosphorylation of PCK1 at Ser90, INSIG1 at Ser207 and INSIG2 at Ser151 is not only positively correlated with the nuclear accumulation of SREBP1 in samples from patients with HCC, but also associated with poor HCC prognosis. Our findings highlight the importance of the protein kinase activity of PCK1 in the activation of SREBPs, lipogenesis and the development of HCC.

DOI: 10.1038/s41586-020-2183-2

Source: https://www.nature.com/articles/s41586-020-2183-2

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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