The role of anti-apoptotic factor 14-3-3 in HIV-1-associated dementia (HAD) pathology : The implication for the therapy

我们之前提出，在HAD患者中，14-3-3蛋白可能是神经细胞破坏速率和数量的可靠标记，因为它们特异性地存在于患者的脑脊液中。另一方面，HIV-1的浸润，如病毒感染的巨噬细胞，穿过受损的血脑屏障（BBB）进入中枢神经系统，随之而来的神经细胞凋亡是HAD的特征性病理表现。在本研究中，我们研究了14-3-3蛋白在HAD这些关键过程中的作用，并阐明了其机制。14-3-3蛋白调控gp120介导的神经细胞凋亡。我们发现，在各种14-3-3亚型中，14-3-3 -3τ在艾滋病合并HAD患者的脑组织中特异性上调。由于病毒包膜糖蛋白gp120已被认为是神经元丢失的重要诱导剂，我们接下来将重点放在14-3-3τ在体外模型细胞培养系统中凋亡中的作用。Gp120诱导α-趋化因子受体介导的HUVEC细胞死亡，增加14-3-3τ的表达。dsRNA对14-3-3τ的处理增强了gp120介导的Bad去磷酸化及其在线粒体中的易位，加速了gp120诱导的细胞凋亡。这些数据表明，14-3-3τ通过负调控bad活性来保护gp120诱导的细胞死亡。14-3-3蛋白调节gp120介导的人脑微血管内皮细胞（HBMEC）之间紧密连接（TJ）的破坏。由于血脑屏障的主要细胞成分HBMEC是第一个暴露于血源性病毒产物/感染细胞的神经细胞，因此血脑屏障完整性的破坏与HAD的发病机制密切相关。越来越多的证据表明，神经毒性病毒蛋白，如gp120和Tat，可以增加内皮细胞的通透性，促进HIV-1通过血脑屏障。我们发现，作为微血管通透性增加的一种新的解释，gp120诱导HBMEC中蛋白酶体降解TJ蛋白，如ZO-1和ZO-2, 14-3-3τ负调控这一过程。这些数据是证明gp120分解血脑屏障分子特性的第一个证据。少

We have previously suggested that, in patients with HAD, 14-3-3 proteins might be reliable markers of the rate and amount of neural cell destruction, since they are present in the CSF of patients isoform specifically. On the other hands, the infiltration of HIV-1, such as by virus-infected macropharges, across the damaged blood-brain barrier (BBB) into the CNS and consequent neural apoptosis are the characteristic pathologic manifestation of HAD. In this study, we have examined the role of 14-3-3 proteins in these critical processes of HAD and clarified their mechanisms.14-3-3 proteins regulate the gp120-mediated apoptosis in neural cells. We found that, among the various 14-3-3 isoforms, 14-3-3τ specifically up-regulated in the brain tissue of AIDS patients with HAD. Since the viral envelope glycoprotein, gp120, has been proposed as a prominent inducer of neuronal loss, we next focused on the role of 14-3-3τ in the apoptosis using in vitro model cell culture system. Gp120 induced the … More α-chemokine receptor-mediated cell death and increased the expression of 14-3-3τ in HUVEC. Treatment of the cells with dsRNA against 14-3-3τ enhanced the gp120-mediated dephosphorylation of Bad and its translocation into the mitochondria, accelerating the gp120-induced apoptosis. These data demonstrate that 14-3-3τ protects against cell death induced by gp120 by a negative regulation of the activity of Bad.14-3-3 proteins regulate the gp120-mediated disruption of tight junction (TJ) between human brain microvascular endothelial cells (HBMEC). Since HBMEC, a major cellular component of the BBB, are the first neural cells to be exposed to blood-borne viral products/-infected cells, the disruption of the BBB integrity is closely relevant to the pathogenesis of HAD. Growing evidences have indicated that neurotoxic viral proteins, such as gp120 and Tat increase endothelial permeability to facilitate the passage of HIV-1 across the BBB. We found that, as a novel explanation for increased microvascular permeability, gp120 induces the degradation of TJ proteins, such as ZO-1 and ZO-2 by the proteasome in HBMEC and 14-3-3τ negatively regulates this process. These data are the first evidence that demonstrates the molecular properties of the BBB breakdown by gp120. Less