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首页> 美国卫生研究院文献>International Journal of Molecular Sciences >Glycogen Synthase Kinase 3 Beta Regulates the Human Aryl Hydrocarbon Receptor Cellular Content and Activity
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Glycogen Synthase Kinase 3 Beta Regulates the Human Aryl Hydrocarbon Receptor Cellular Content and Activity

机译：糖原合成酶激酶3β调节人芳基烃受体细胞含量和活性

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The aryl hydrocarbon receptor (AHR) is a cytosolic receptor which is involved in diverse cellular events in humans. The most well-characterized function of AHR is its ability to upregulate gene transcription after exposure to its ligands, such as environmental toxicants, dietary antioxidants, drugs, and endogenous ligands. The cellular content of AHR is partly controlled by its degradation via the ubiquitin–proteasome system and the lysosome-dependent autophagy. We used human cervical cancer (HeLa) cells to investigate how AHR undergoes protein degradation and how its activity is modulated. Since the glycogen synthase kinase 3 beta (GSK3β)-mediated phosphorylation can trigger protein degradation and substrates of GSK3β contain stretches of serine/threonine residues which can be found in AHR, we examined whether degradation and activity of AHR can be controlled by GSK3β. We observed that AHR undergoes the GSK3β-dependent, LC3-mediated lysosomal degradation without ligand treatment. The AHR can be phosphorylated in a GSK3β-dependent manner at three putative sites (S436/S440/S444, S689/S693/T697, and S723/S727/T731), which leads to lysosomal degradation of the AHR protein. Inhibition of the GSK3β activity suppresses the ligand-activated transcription of an AHR target gene in HeLa, human liver cancer (Hep3B), and human breast cancer (MCF-7) cells. Collectively, our findings support that phosphorylation of AHR by GSK3β is essential for the optimal activation of its target gene transcription and this phosphorylation may partake as an “off” switch by subjecting the receptor to lysosomal degradation.
机译：芳基烃受体（AHR）是一种胞质受体，其参与人体中的多种细胞事件。 AHR最​​良好表征的功能是其在暴露于其配体之后提起基因转录的能力，例如环境毒物，膳食抗氧化剂，药物和内源性配体。 AHR的细胞含量部分地通过遍突蛋白 - 蛋白酶体系和溶酶体依赖性自噬的降解来控制。我们使用人宫颈癌（HELA）细胞来研究AHR如何经历蛋白质降解以及其活性的调节方式。由于糖原合酶激酶3β（GSK3β）介导的磷酸化可以触发蛋白降解和GSK3β的基板含有可在AHR中找到的丝氨酸/苏氨酸残基的延伸，我们检查是否AHR的降解和活性可以通过GSK3β进行控制。我们观察到AHR经历了GSK3β依赖性的LC3介导的溶酶体降解，无配体处理。 AHR可以在三个推定位置以GSK3β依赖性方式磷酸化（S436 / S440 / S444，S689 / S693 / T697和S723 / S727 / T731），这导致AHR蛋白的溶酶体降解。 GSK3β活性的抑制抑制了HeLa，人肝癌（HEP3B）和人乳腺癌（MCF-7）细胞中AHR靶基因的配体活化转录。统称，我们的研究结果支持GSK3β的AHR磷酸化对于其靶基因转录的最佳活化是必不可少的，并且这种磷酸化可以通过使受体对溶酶体降解来分析为“关”开关。

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