Activation of Chaperone-Mediated Autophagy Inhibits the Aryl Hydrocarbon Receptor Function by Degrading This Receptor in Human Lung Epithelial Carcinoma A549 Cells.
Activation of Chaperone-Mediated Autophagy Inhibits the Aryl Hydrocarbon Receptor Function by Degrading This Receptor in Human Lung Epithelial Carcinoma A549 Cells.
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DOI：
10.3390/ijms242015116
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发表时间：
2023-10-12
影响因子：
5.6
通讯作者：
Chan WK
中科院分区：
文献类型：
--
作者：
Xiong R;Shao D;Do S;Chan WK
芳烃受体 (AHR) 是一种配体激活的转录因子，也是负责多种细胞过程的 Cullin 4B E3 连接酶复合物的底物蛋白。在肺部，该受体负责肿瘤发生过程中苯并[a]芘的生物激活。认识到 AHR 功能受其表达水平影响，我们对 AHR 在肺中的降解机制感兴趣。在这里，我们使用人肺上皮 A549 细胞研究了 AHR 降解的机制。我们观察到，在存在自噬抑制剂氯喹 (CQ) 的情况下，AHR 蛋白水平以剂量依赖性方式增加。用 6-氨基烟酰胺 (6-AN)（一种分子伴侣介导的自噬 (CMA) 激活剂）治疗，可以浓度依赖性和时间依赖性方式降低 AHR 蛋白水平。这种减少抑制了 AHR 靶基因转录的配体依赖性激活，并且可以被 CQ 逆转，但不能被 MG132 逆转。敲低溶酶体相关膜蛋白 2 (LAMP2)，但不敲低自噬相关膜蛋白 5 (ATG5)，可抑制氯喹介导的 AHR 蛋白增加。当 AHR 的 CMA 基序发生突变时，AHR 对 CMA 具有抗性。当 AHR 基因被敲除或 6-AN 降低 AHR 蛋白水平时，可以观察到 A549 细胞中上皮-间质转化的抑制。总的来说，我们提供的证据支持 AHR 持续经历 CMA，并且 CMA 的激活抑制 A549 细胞中的 AHR 功能。
The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and a substrate protein of a Cullin 4B E3 ligase complex responsible for diverse cellular processes. In the lung, this receptor is responsible for the bioactivation of benzo[a]pyrene during tumorigenesis. Realizing that the AHR function is affected by its expression level, we are interested in the degradation mechanism of AHR in the lung. Here, we have investigated the mechanism responsible for AHR degradation using human lung epithelial A549 cells. We have observed that the AHR protein levels increase in the presence of chloroquine (CQ), an autophagy inhibitor, in a dose-dependent manner. Treatment with 6-aminonicotinamide (6-AN), a chaperone-mediated autophagy (CMA) activator, decreases AHR protein levels in a concentration-dependent and time-dependent manner. This decrease suppresses the ligand-dependent activation of the AHR target gene transcription, and can be reversed by CQ but not MG132. Knockdown of lysosome-associated membrane protein 2 (LAMP2), but not autophagy-related 5 (ATG5), suppresses the chloroquine-mediated increase in the AHR protein. AHR is resistant to CMA when its CMA motif is mutated. Suppression of the epithelial-to-mesenchymal transition in A549 cells is observed when the AHR gene is knocked out or the AHR protein level is reduced by 6-AN. Collectively, we have provided evidence supporting that AHR is continuously undergoing CMA and activation of CMA suppresses the AHR function in A549 cells.
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影响因子：
13.3
作者：
Finn, Patrick E.;Mesires, Nicholas T.;Dice, J. Fred
通讯作者：
Dice, J. Fred
EMT亚型影响上皮可塑性和细胞迁移模式。
影响因子：
11.8
作者：
Aiello NM;Maddipati R;Norgard RJ;Balli D;Li J;Yuan S;Yamazoe T;Black T;Sahmoud A;Furth EE;Bar-Sagi D;Stanger BZ
通讯作者：
Stanger BZ
影响因子：
11.1
作者：
Harhouri K;Navarro C;Depetris D;Mattei MG;Nissan X;Cau P;De Sandre-Giovannoli A;Lévy N
通讯作者：
Lévy N
影响因子：
5.6
作者：
通讯作者：
--
影响因子：
13.3
作者：
Ferreira, Joao Vasco;Fofo, Hugo;Pereira, Paulo
通讯作者：
Pereira, Paulo