Alcohol-induced tubulin post-translational modifications directly alter hepatic protein trafficking.
Alcohol-induced tubulin post-translational modifications directly alter hepatic protein trafficking.
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DOI：
10.1097/hc9.0000000000000103
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发表时间：
2023-04-01
影响因子：
5.1
通讯作者：
中科院分区：
文献类型：
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作者：
慢性乙醇暴露导致蛋白质乙酰化和乙醛加合增强。在乙醇给药后修饰的众多蛋白质中，微管蛋白是研究得最好的。然而，一个悬而未决的问题是，是否在患者样本中观察到这些修饰。这两种修饰也与促进酒精诱导的蛋白质运输缺陷有关，但它们是否直接如此也没有答案。我们首先证实，微管蛋白是高度乙酰化和乙酰丙酮化物de-adducted从乙醇暴露的个人在肝脏中观察到类似的程度，从乙醇喂养的动物和肝细胞的肝脏。非酒精相关性脂肪肝个体的肝脏显示微管蛋白乙酰化适度增加，而非酒精相关性纤维化人类和小鼠肝脏几乎没有显示微管蛋白修饰。我们还询问了微管蛋白乙酰化或乙醛加合是否可以直接解释已知的酒精诱导的蛋白质运输缺陷。乙酰化通过过度表达α-微管蛋白特异性乙酰转移酶α TAT 1诱导，而内收通过直接向细胞中加入乙醛诱导。α TAT 1过表达和乙醛处理均显著损害正端（分泌）和负端（转胞吞）导向的微管依赖性运输和网格蛋白介导的内吞作用。每种修饰导致与乙醇处理的细胞中观察到的相似水平的损伤。通过任一修饰的损伤水平显示无剂量依赖性或无累加效应，表明亚化学计量微管蛋白修饰导致改变的蛋白质运输，并且赖氨酸未被选择性地修饰。这些结果不仅证实了在人类肝脏中观察到增强的微管蛋白乙酰化，而且它与酒精诱导的损伤最相关。由于这些微管蛋白的修饰与改变蛋白质运输，改变适当的肝功能，我们建议改变细胞乙酰化水平或清除游离醛是治疗酒精相关性肝病的可行策略。
Chronic ethanol exposure leads to enhanced protein acetylation and acetaldehyde adduction. Of the multitude of proteins that are modified on ethanol administration, tubulin is among the best studied. However, an open question is whether these modifications are observed in patient samples. Both modifications have also been implicated in promoting alcohol-induced defects in protein trafficking, but whether they do so directly is also unanswered. We first confirmed that tubulin was hyperacetylated and acetaldehyde-adducted in the livers from ethanol-exposed individuals to a similar extent as observed in the livers from ethanol-fed animals and hepatic cells. Livers from individuals with nonalcohol-associated fatty liver showed modest increases in tubulin acetylation, whereas nonalcohol-associated fibrotic human and mouse livers showed virtually no tubulin modifications. We also asked whether tubulin acetylation or acetaldehyde adduction can directly explain the known alcohol-induced defects in protein trafficking. Acetylation was induced by overexpressing the α-tubulin–specific acetyltransferase, αTAT1, whereas adduction was induced by directly adding acetaldehyde to cells. Both αTAT1 overexpression and acetaldehyde treatment significantly impaired plus-end (secretion) and minus-end (transcytosis)–directed microtubule-dependent trafficking and clathrin-mediated endocytosis. Each modification led to similar levels of impairment as observed in ethanol-treated cells. The levels of impairment by either modification showed no dose dependence or no additive effects suggesting that substoichiometric tubulin modifications lead to altered protein trafficking and that lysines are not selectively modified. These results not only confirm that enhanced tubulin acetylation is observed in human livers but that it is most relevant to alcohol-induced injury. Because these tubulin modifications are associated with altered protein trafficking that alters proper hepatic function, we propose that changing the cellular acetylation levels or scavenging free aldehydes are feasible strategies for treating alcohol-associated liver disease.
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影响因子：
7.8
作者：
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影响因子：
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通讯作者：
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