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首页> 外文期刊>American Journal of Physiology >The aryl hydrocarbon receptor reduces LC3II expression and controls endoplasmic reticulum stress
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The aryl hydrocarbon receptor reduces LC3II expression and controls endoplasmic reticulum stress

机译：芳基烃受体减少了LC3II表达并对照组内质网胁迫

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摘要

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor whose physiological function is poorly understood. The AhR is highly expressed in barrier organs such as the skin, intestine, and lung. The lungs are continuously exposed to environmental pollutants such as cigarette smoke (CS) that can induce cell death mechanisms such as apoptosis, autophagy, and endoplasmic reticulum (ER) stress. CS also contains toxicants that are AhR ligands. We have previously shown that the AhR protects against apoptosis, but whether the AhR also protects against autophagy or ER stress is not known. Using cigarette smoke extract (CSE) as our in vitro surrogate of environmental tobacco exposure, we first assessed the conversion of LC3I to LC3II, a classic feature of both autophagic and ER stress-mediated cell death pathways. LC3II was elevated in CSE-exposed lung structural cells [mouse lung fibroblasts (MLFs), MLE12 and A549 cells] when AhR was absent. However, this heightened LC3II expression could not be explained by increased expression of key autophagy genes (GabarapH, Becn1, Map1lc3b), upregulation of upstream autophagic machinery (Atg5-12, Atg3), or impaired autophagic flux, suggesting that LC3II may be autophagy independent. This was further supported by the absence of autophagosomes in Ahr~-/- lung cells. However, Ahr~-/- lung cells had widespread ER dilation, elevated expression of the ER stress markers CHOP and GADD34, and an accumulation of ubiquitinated proteins. These findings collectively illustrate a novel role for the AhR in attenuating ER stress by a mechanism that may be autophagy independent.
机译：芳香烃受体（AhR）是一种配体激活的转录因子，其生理功能尚不清楚。AhR在皮肤、肠道和肺等屏障器官中高度表达。肺部持续暴露于环境污染物，如香烟烟雾（CS），可诱导细胞凋亡、自噬和内质网（ER）应激等细胞死亡机制。CS还含有作为AhR配体的毒物。我们之前已经证明AhR可以防止细胞凋亡，但AhR是否也可以防止自噬或内质网应激尚不清楚。使用香烟烟雾提取物（CSE）作为环境烟草暴露的体外替代物，我们首先评估了LC3I向LC3II的转化，这是自噬和内质网应激介导的细胞死亡途径的经典特征。当缺乏AhR时，CSE暴露的肺结构细胞[小鼠肺成纤维细胞（MLF）、MLE12和A549细胞]中的LC3II升高。然而，关键自噬基因（GabarapH、Becn1、Map1lc3b）的表达增加、上游自噬机制（Atg5-12、Atg3）的上调或自噬通量受损并不能解释LC3II表达的增加，这表明LC3II可能与自噬无关。Ahr~-/-肺细胞中缺乏自噬体进一步证实了这一点。然而，Ahr~-/-肺细胞具有广泛的内质网扩张，内质网应激标记物CHOP和GADD34的表达升高，以及泛素化蛋白的积累。这些发现共同说明了AhR通过一种可能与自噬无关的机制在减轻内质网应激中的新作用。

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