High Mobility Group Box 1 Release from Hepatocytes during Ischemia and Reperfusion Injury Is Mediated by Decreased Histone Deacetylase Activity
High Mobility Group Box 1 Release from Hepatocytes during Ischemia and Reperfusion Injury Is Mediated by Decreased Histone Deacetylase Activity
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DOI：
10.1074/jbc.m110.128348
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发表时间：
2010-12-17
影响因子：
4.8
通讯作者：
Tsung, Allan
中科院分区：
文献类型：
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作者：
Evankovich, John;Cho, Sung W.;Tsung, Allan
缺血细胞对核高迁移率族蛋白B1（HMGB1）的动员及细胞外释放会在肝脏缺血/再灌注（I/R）损伤后激活炎症通路。在巨噬细胞等免疫细胞中，乙酰化这种翻译后修饰似乎对HMGB1的活性释放至关重要。高度乙酰化使其平衡从主要的核定位转向胞质积累以及随后的释放。然而，调控实质细胞（如肝细胞）释放HMGB1的机制尚不清楚。在本研究中，我们发现体内肝脏I/R后释放的血清HMGB1是乙酰化的，并且体外暴露于氧化应激的肝细胞也会释放乙酰化的HMGB1。组蛋白去乙酰化酶（HDACs）是一类去除乙酰基并控制组蛋白和各种细胞内蛋白质乙酰化状态的酶。乙酰化HMGB1的水平升高，同时总核HDAC活性降低，这表明HDAC活性的抑制有助于肝细胞在氧化应激后乙酰化HMGB1释放的增加。我们确定HDAC1和HDAC4异构体在调节乙酰化HMGB1释放中起关键作用。在遭受氧化应激的肝细胞的细胞核中，HDAC1的激活降低。此外，用小干扰RNA（siRNA）敲低HDAC1促进了HMGB1的易位和释放。再者，我们证明HDAC4会响应氧化应激从细胞核穿梭至细胞质，导致细胞核中HDAC活性降低。总之，这些发现表明肝脏I/R后肝细胞中核HDAC1和HDAC4活性降低是一种促进HMGB1高度乙酰化及随后释放的机制。
The mobilization and extracellular release of nuclear high mobility group box-1 (HMGB1) by ischemic cells activates inflammatory pathways following liver ischemia/reperfusion (I/R) injury. In immune cells such as macrophages, post-translational modification by acetylation appears to be critical for active HMGB1 release. Hyperacetylation shifts its equilibrium from a predominant nuclear location toward cytosolic accumulation and subsequent release. However, mechanisms governing its release by parenchymal cells such as hepatocytes are unknown. In this study, we found that serum HMGB1 released following liver I/R in vivo is acetylated, and that hepatocytes exposed to oxidative stress in vitro also released acetylated HMGB1. Histone deacetylases (HDACs) are a family of enzymes that remove acetyl groups and control the acetylation status of histones and various intracellular proteins. Levels of acetylated HMGB1 increased with a concomitant decrease in total nuclear HDAC activity, suggesting that suppression in HDAC activity contributes to the increase in acetylated HMGB1 release after oxidative stress in hepatocytes. We identified the isoforms HDAC1 and HDAC4 as critical in regulating acetylated HMGB1 release. Activation of HDAC1 was decreased in the nucleus of hepatocytes undergoing oxidative stress. In addition, HDAC1 knockdown with siRNA promoted HMGB1 translocation and release. Furthermore, we demonstrate that HDAC4 is shuttled from the nucleus to cytoplasm in response to oxidative stress, resulting in decreased HDAC activity in the nucleus. Together, these findings suggest that decreased nuclear HDAC1 and HDAC4 activities in hepatocytes following liver I/R is a mechanism that promotes the hyperacetylation and subsequent release of HMGB1.