Occludin controls HIV transcription in brain pericytes via regulation of SIRT-1 activation
Occludin controls HIV transcription in brain pericytes via regulation of SIRT-1 activation
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DOI：
10.1096/fj.15-277673
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发表时间：
2016-03-01
期刊：
影响因子：
4.8
通讯作者：
Toborek, Michal
中科院分区：
文献类型：
--
作者：
Castro, Victor;Bertrand, Luc;Toborek, Michal
HIV在感染后早期侵入大脑；然而，其与血脑屏障（BBB）细胞的相互作用仍然知之甚少。我们的目的是评估occludin的作用，occludin是一种紧密连接蛋白，在血脑屏障周细胞的HIV感染中调节血脑屏障功能。我们提供的证据表明，occludin水平在很大程度上控制了人类周细胞对HIV的代谢反应。在HIV感染后的头48小时内，血脑屏障周细胞中的Occludin减少了10%，这与基因抑制因子c -末端结合蛋白(CtBP)-1的核易位增加和NF κ pa B-p65的激活有关。这些变化与III类组蛋白去乙酰化酶sirtuin (SIRT)-1的表达和激活降低有关。Occludin水平在感染96小时后恢复，SIRT-1恢复，HIV转录降低到其最高值的20%。我们将occludin定性为一种控制SIRT-1表达和激活的新型NADH氧化酶。随后在人原代巨噬细胞和分化的单核细胞U937中复制了occludin与HIV转录的负相关，其中occludin沉默分别导致75%和250%的病毒转录增加。我们的工作表明，闭塞蛋白具有以前未被怀疑的代谢特性，并且是HIV感染的靶标，这为设计新的药理学方法来控制HIV转录打开了可能性。
HIV invades the brain early after infection; however, its interactions with the cells of the blood-brain barrier (BBB) remain poorly understood. Our goal was to evaluate the role of occludin, one of the tight junction proteins that regulate BBB functions in HIV infection of BBB pericytes. We provide evidence that occludin levels largely control the metabolic responses of human pericytes to HIV. Occludin in BBB pericytes decreased by 10% during the first 48 h after HIV infection, correlating with increased nuclear translocation of the gene repressor C-terminal-binding protein (CtBP)-1 and NF kappa B-p65 activation. These changes were associated with decreased expression and activation of the class III histone deacetylase sirtuin (SIRT)-1. Occludin levels recovered 96 h after infection, restoring SIRT-1 and reducing HIV transcription to 20% of its highest values. We characterized occludin biochemically as a novel NADH oxidase that controls the expression and activation of SIRT-1. The inverse correlation between occludin and HIV transcription was then replicated in human primary macrophages and differentiated monocytic U937 cells, in which occludin silencing resulted in 75 and 250% increased viral transcription, respectively. Our work shows that occludin has previously unsuspected metabolic properties and is a target of HIV infection, opening the possibility of designing novel pharmacological approaches to control HIV transcription.