HIV-1 Tat Alters Neuronal Autophagy by Modulating Autophagosome Fusion to the Lysosome: Implications for HIV-Associated Neurocognitive Disorders
HIV-1 Tat Alters Neuronal Autophagy by Modulating Autophagosome Fusion to the Lysosome: Implications for HIV-Associated Neurocognitive Disorders
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DOI：
10.1523/jneurosci.3207-14.2015
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发表时间：
2015-02-04
影响因子：
5.3
通讯作者：
Masliah, Eliezer
中科院分区：
文献类型：
--
作者：
Fields, Jerel;Dumaop, Wilmar;Masliah, Eliezer
抗逆转录病毒疗法延长了艾滋病病毒（HIV）感染者的寿命；然而，在老年HIV患者中，艾滋病相关神经认知障碍（HAND）的发病率正在上升。先前的研究表明，HIV感染会改变衰老中枢神经系统（CNS）的自噬功能，并且HIV - 1蛋白会影响单核细胞衍生细胞的自噬。尽管有这些发现，但导致中枢神经系统自噬失调的机制仍不清楚。在此，我们试图确定HIV Tat蛋白如何失调神经元中的自噬。Tat导致膜富集组分中自噬体标记物微管相关蛋白1轻链βII（LC3II）和自噬受体蛋白1（SQSTM1）呈剂量依赖性减少，这表明Tat增加了自噬降解。巴弗洛霉素A1增加了自噬体数量、LC3II和SQSTM1的积累；Tat共同处理减弱了这种效应。当3 - 甲基腺嘌呤阻断自噬早期阶段或敲低贝林1（beclin 1）时，Tat没有作用。Tat增加了LC3斑点的数量，并导致体外异常自噬体的形成。同样，在胶质纤维酸性蛋白 - Tat转基因（GFAP - Tat tg）小鼠体内的研究显示，神经元中自噬体积累增加，LC3II水平改变以及神经退行性变。雷帕霉素治疗可逆转这些效应。Tat与自噬体和溶酶体标记物共定位，并增强了自噬体与溶酶体标记物的共定位。此外，免疫共沉淀（co - IP）研究表明，Tat在体外和体内都与溶酶体相关膜蛋白2A（LAMP2A）相互作用，并且LAMP2A过表达可降低Tat诱导的神经毒性。因此，Tat蛋白可能通过与LAMP2A相互作用诱导自噬体和溶酶体融合，从而导致神经元自噬功能异常以及关键细胞内成分的降解失调。针对Tat介导的自噬改变的疗法可能会减少患有HAND的老年患者的神经退行性变。
Antiretroviral therapy has increased the life span of HIV + individuals; however, HIV-associated neurocognitive disorder (HAND) occurrence is increasing in aging HIV patients. Previous studies suggest HIV infection alters autophagy function in the aging CNS and HIV-1 proteins affect autophagy in monocyte-derived cells. Despite these findings, the mechanisms leading to dysregulated autophagy in the CNS remain unclear. Here we sought to determine how HIV Tat dysregulates autophagy in neurons. Tat caused a dose-dependent decrease in autophagosome markers, microtubule-associated protein-1 light chain beta II (LC3II), and sequestosome 1(SQSTM1), in a membrane-enriched fraction, suggesting Tat increases autophagic degradation. Bafilomycin A1 increased autophagosome number, LC3II, and SQSTM1 accumulation; Tat cotreatment diminished this effect. Tat had no effect when 3-methyladenine or knockdown of beclin 1 blocked early stages of autophagy. Tat increased numbers of LC3 puncta and resulted in the formation of abnormal autophagosomes in vitro. Likewise, in vivo studies in GFAP-Tat tg mice showed increased autophagosome accumulation in neurons, altered LC3II levels, and neurodegeneration. These effects were reversed by rapamycin treatment. Tat colocalized with autophagosome and lysosomal markers and enhanced the colocalization of autophagosome with lysosome markers. Furthermore, co-IP studies showed that Tat interacts with lysosomal-associated membrane protein 2A (LAMP2A) in vitro and in vivo, and LAMP2A overexpression reduces Tat-induced neurotoxicity. Hence, Tat protein may induce autophagosome and lysosome fusion through interaction with LAMP2A leading to abnormal neuronal autophagy function and dysregulated degradation of critical intracellular components. Therapies targeting Tat-mediated autophagy alterations may decrease neurodegeneration in aging patients with HAND.