Lysine acetylation induced by chronic ethanol consumption impairs dynamin-mediated clathrin-coated vesicle release.
Lysine acetylation induced by chronic ethanol consumption impairs dynamin-mediated clathrin-coated vesicle release.
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DOI：
10.1002/hep.24785
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发表时间：
2012-04
期刊：
影响因子：
13.5
通讯作者：
Tuma, Pamela L.
中科院分区：
文献类型：
--
作者：
Shepard, Blythe D.;Tuma, Dean J.;Tuma, Pamela L.
肝脏是乙醇代谢的主要部位，因此，长期饮酒对肝脏的损伤最大。肝细胞的乙醇代谢导致活性代谢物和氧自由基的产生，这些代谢物和氧自由基可以容易地加合DNA、脂质和蛋白质。最近，已经变得明显的是，乙醇消耗也导致天然库的翻译后修饰增加，包括赖氨酸超乙酰化。以前，我们确定酒精消费选择性损害网格蛋白介导的极化肝细胞的内化。然而，无论是发生阻塞的步骤还是造成缺陷的机制都没有被确定。为了确定网格蛋白介导的内化受损的具体步骤，我们检查了控制和乙醇处理的细胞中网格蛋白机械的选定组件的分布、水平和组装。为了确定损伤是否是由于乙醇诱导的赖氨酸乙酰化，我们还检查了相同的外壳组件在处理细胞中的阿司他丁A（TSA），脱乙酰酶抑制剂，导致蛋白质超乙酰化在乙醇的情况下。我们确定，乙醇和TSA损害内化在后期囊泡分裂之前。我们进一步确定这种缺陷可能是由于网格蛋白包被的内陷的颈部的发动蛋白募集减少导致囊泡出芽受损。这些结果也提出了令人兴奋的可能性，即促进赖氨酸脱乙酰化的药物可能是治疗酒精性肝病的有效治疗剂。
The liver is the major site of ethanol metabolism, and thus, sustains the most injury from chronic alcohol consumption. Ethanol metabolism by the hepatocyte leads to the generation of reactive metabolites and oxygen radicals that can readily adduct DNA, lipids and proteins. More recently, it has become apparent that ethanol consumption also leads to increased post-translational modifications of the natural repertoire including lysine hyperacetylation. Previously, we determined that alcohol consumption selectively impairs clathrin-mediated internalization in polarized hepatocytes. However, neither the step at which the block occurs nor the mechanism responsible for the defect have been identified. To identify the specific step at which clathrin-mediated internalization is impaired, we examined the distributions, levels and assembly of selected components of the clathrin machinery in control and ethanol-treated cells. To determine whether the impairment is due to ethanol-induced lysine acetylation, we also examined the same coat components in cells treated with trichostatin A (TSA), a deacetylase inhibitor that leads to protein hyperacetylation in the absence of ethanol. We determined that both ethanol and TSA impair internalization at a late stage prior to vesicle fission. We further determined that this defect is likely due to decreased dynamin recruitment to the necks of clathrin-coated invaginations resulting in impaired vesicle budding. These results also raise the exciting possibility that agents that promote lysine deacetylation may be effective therapeutics for the treatment of alcoholic liver disease.
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WIF-B细胞：用于研究肝细胞极性的体外模型。
影响因子：
7.8
作者：
Ihrke, G;Neufeld, E B;Meads, T;Shanks, M R;Cassio, D;Laurent, M;Schroer, T A;Pagano, R E;Hubbard, A L
通讯作者：
Hubbard, A L
突变动力蛋白的诱导特异性阻断内吞涂层囊泡的形成。
影响因子：
7.8
作者：
Damke, H;Baba, T;Warnock, D E;Schmid, S L
通讯作者：
Schmid, S L
影响因子：
6.1
作者：
JENNETT, RB;SAFFARIFARD, A;TUMA, DJ
通讯作者：
TUMA, DJ
影响因子：
11.8
作者：
Macia, Eric;Ehrlich, Marcelo;Kirchhausen, Tomas
通讯作者：
Kirchhausen, Tomas
DOI：
10.1073/pnas.86.13.4968
发表时间：
1989-07-01
影响因子：
11.1
作者：
KESSELL, I;HOLST, BD;ROTH, TF
通讯作者：
ROTH, TF