Alcohol-Induced Liver Injury: Down-regulation and Redistribution of Rab3D Results in Atypical Protein Trafficking.
Alcohol-Induced Liver Injury: Down-regulation and Redistribution of Rab3D Results in Atypical Protein Trafficking.
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DOI：
10.1002/hep4.1811
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发表时间：
2022-03
影响因子：
5.1
通讯作者：
Petrosyan A
中科院分区：
文献类型：
--
作者：
Casey CA;Macke AJ;Gough RR;Pachikov AN;Morris ME;Thomes PG;Kubik JL;Holzapfel MS;Petrosyan A
我们实验室以前的工作已经确定了内吞、蛋白质运输和分泌的多种缺陷，沿着酒精给药后高尔基体功能的改变。酒精相关性肝病（ALD）的表现与几种肝脏蛋白的异常功能有关，包括脱唾液酸糖蛋白受体（ASGP-R），它们在质膜（PM）上的非典型分布，以及它们异常糖基化形式分泌到血流中，但运输机制尚不清楚。在这里，我们报告说，一个小的GTdR，Rab 3D，已知参与胞吐，分泌和囊泡贩运，显示乙醇（EtOH）受损的功能，这在高尔基体解体中起着重要的作用。我们使用多种方法和ALD的细胞/动物模型，沿着Rab 3D敲除（KO）小鼠和来自ALD患者的人组织。我们发现Rab 3D主要存在于高尔基体的反式和顺式表面;然而，EtOH处理导致Rab 3D从反式高尔基体重新分布到顺式中间高尔基体。缺乏Rab 3D的细胞表现出高尔基体的扩大，特别是其远端隔室。我们发现Rab 3D是高尔基体中外壳蛋白I（COPI）囊泡形成所必需的，相反，COPI对Rab 3D的高尔基体内分布至关重要。Rab 3D/COPI关联不仅在ALD患者的肝脏中改变，而且在饮酒而无脂肪变性的供体中也改变。在Rab 3D KO小鼠中，肝细胞经历内质网（ER）应激，EtOH给药激活细胞凋亡。值得注意的是，在这些细胞中，尽管糖基化不完全，ASGP-R仍然可以通过ER-PM连接到达细胞表面。这模拟了EtOH诱导的肝损伤所见的效应。结论：我们发现Rab 3D的下调显著促进了EtOH诱导的高尔基体解体，并且异常糖基化的ASGP‐R通过ER‐PM连接排泄，绕过了经典的（ER→高尔基体→PM）顺行运输。这表明ER-PM位点可能是ALD的治疗靶点。我们发现Rab 3D的下调对EtOH诱导的高尔基体紊乱有显著贡献，异常糖基化的ASGP-R的异常排泄与ER-PM连接的形成有关，绕过了经典的顺行运输。这表明ER-PM位点可能是ALD的新治疗靶点。
Previous work from our laboratories has identified multiple defects in endocytosis, protein trafficking, and secretion, along with altered Golgi function after alcohol administration. Manifestation of alcohol‐associated liver disease (ALD) is associated with an aberrant function of several hepatic proteins, including asialoglycoprotein receptor (ASGP‐R), their atypical distribution at the plasma membrane (PM), and secretion of their abnormally glycosylated forms into the bloodstream, but trafficking mechanism is unknown. Here we report that a small GTPase, Rab3D, known to be involved in exocytosis, secretion, and vesicle trafficking, shows ethanol (EtOH)–impaired function, which plays an important role in Golgi disorganization. We used multiple approaches and cellular/animal models of ALD, along with Rab3D knockout (KO) mice and human tissue from patients with ALD. We found that Rab3D resides primarily in trans‐ and cis‐faces of Golgi; however, EtOH treatment results in Rab3D redistribution from trans‐Golgi to cis‐medial‐Golgi. Cells lacking Rab3D demonstrate enlargement of Golgi, especially its distal compartments. We identified that Rab3D is required for coat protein I (COPI) vesiculation in Golgi, and conversely, COPI is critical for intra‐Golgi distribution of Rab3D. Rab3D/COPI association was altered not only in the liver of patients with ALD but also in the donors consuming alcohol without steatosis. In Rab3D KO mice, hepatocytes experience endoplasmic reticulum (ER) stress, and EtOH administration activates apoptosis. Notably, in these cells, ASGP‐R, despite incomplete glycosylation, can still reach cell surface through ER‐PM junctions. This mimics the effects seen with EtOH‐induced liver injury. Conclusion : We revealed that down‐regulation of Rab3D contributes significantly to EtOH‐induced Golgi disorganization, and abnormally glycosylated ASGP‐R is excreted through ER‐PM connections, bypassing canonical (ER→Golgi→PM) anterograde transportation. This suggests that ER‐PM sites may be a therapeutic target for ALD. We revealed that downregulation of Rab3D contributes significantly to EtOH‐induced Golgi disorganization, and aberrant excretion of abnormally glycosylated ASGP‐R is linked to formation of ER‐PM connections, bypassing canonical anterograde transportation. This suggests that ER‐PM sites may be a novel therapeutic target for ALD.
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影响因子：
5.2
作者：
Manca, Sonia;Frisbie, Cole P.;Petrosyan, Armen
通讯作者：
Petrosyan, Armen
影响因子：
4
作者：
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影响因子：
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作者：
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影响因子：
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作者：
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