Glycogen Synthase Kinase 3 Beta Regulates the Human Aryl Hydrocarbon Receptor Cellular Content and Activity.
Glycogen Synthase Kinase 3 Beta Regulates the Human Aryl Hydrocarbon Receptor Cellular Content and Activity.
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DOI：
10.3390/ijms22116097
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发表时间：
2021-06-05
影响因子：
5.6
通讯作者：
Chan WK
中科院分区：
文献类型：
--
作者：
Yang Y;Chan WK
芳烃受体（AHR）是一种细胞质受体，参与人体多种细胞活动。AHR最广为人知的功能是它在暴露于其配体（如环境毒物、膳食抗氧化剂、药物和内源性配体）后上调基因转录的能力。AHR的细胞含量部分受其通过泛素-蛋白酶体系统和溶酶体依赖性自噬的降解控制。我们使用人宫颈癌（HeLa）细胞来研究AHR如何经历蛋白质降解及其活性如何被调节。由于糖原合成酶激酶3β (GSK3β)介导的磷酸化可以触发蛋白质降解，并且GSK3β的底物含有在AHR中发现的丝氨酸/苏氨酸残基的延伸，我们研究了GSK3β是否可以控制AHR的降解和活性。我们观察到AHR在没有配体处理的情况下经历gsk3 β依赖、lc3介导的溶酶体降解。AHR可以在三个假定的位点（S436/S440/S444， S689/S693/T697和S723/S727/T731）以依赖gsk3 β的方式磷酸化，从而导致AHR蛋白的溶酶体降解。抑制GSK3β活性可抑制HeLa、人肝癌（Hep3B）和人乳腺癌（MCF-7）细胞中AHR靶基因的配体激活转录。总的来说，我们的研究结果支持GSK3β对AHR的磷酸化对于其靶基因转录的最佳激活是必不可少的，并且这种磷酸化可能通过使受体受到溶酶体降解而参与“关闭”开关。
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.
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影响因子：
64.8
作者：
Jia, JH;Amanal, K;Jiang, J
通讯作者：
Jiang, J
影响因子：
25
作者：
Giovannoni F;Bosch I;Polonio CM;Torti MF;Wheeler MA;Li Z;Romorini L;Rodriguez Varela MS;Rothhammer V;Barroso A;Tjon EC;Sanmarco LM;Takenaka MC;Modaresi SMS;Gutiérrez-Vázquez C;Zanluqui NG;Dos Santos NB;Munhoz CD;Wang Z;Damonte EB;Sherr D;Gehrke L;Peron JPS;Garcia CC;Quintana FJ
通讯作者：
Quintana FJ
影响因子：
5.6
作者：
Chen J;Yang Y;Russu WA;Chan WK
通讯作者：
Chan WK
影响因子：
16
作者：
Korolchuk, Viktor I.;Mansilla, Alicia;Menzies, Fiona M.;Rubinsztein, David C.
通讯作者：
Rubinsztein, David C.
影响因子：
3.5
作者：
Castañeda AR;Pinkerton KE;Bein KJ;Magaña-Méndez A;Yang HT;Ashwood P;Vogel CFA
通讯作者：
Vogel CFA