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

抗凋亡因子 14-3-3 在 HIV-1 相关痴呆 (HAD) 病理学中的作用：治疗的意义

• 批准号: 17591044
• 负责人: YANO Mihiro
• 金额: $ 2.18万
• 依托单位: The University of Tokushima
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591044/
• 关键词: HIV-1-associated dementia (HAD); 14-3-3 protein; Neuronal cell death; Blood-brain barrier (BBB); Tight Junction; proteasome

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

我们之前曾提出，在 HAD 患者中，14-3-3 蛋白可能是神经细胞破坏率和数量的可靠标记，因为它们特异性地存在于患者亚型的 CSF 中。另一方面，HIV-1 的渗透（例如通过病毒感染的巨噬细胞）穿过受损的血脑屏障（BBB）进入 CNS 并随之发生的神经细胞凋亡是 HAD 的特征性病理表现。在这项研究中，我们研究了14-3-3蛋白在HAD这些关键过程中的作用，并阐明了它们的机制。14-3-3蛋白调节gp120介导的神经细胞凋亡。我们发现，在各种 14-3-3 异构体中，14-3-3τ 在患有 HAD 的 AIDS 患者的脑组织中特异性上调。由于病毒包膜糖蛋白 gp120 被认为是神经元丢失的重要诱导剂，因此我们接下来使用体外模型细胞培养系统重点研究 14-3-3τ 在细胞凋亡中的作用。 Gp120 诱导 α-趋化因子受体介导的细胞死亡并增加 HUVEC 中 14-3-3τ 的表达。用针对 14-3-3τ 的 dsRNA 处理细胞增强了 gp120 介导的 Bad 去磷酸化及其易位到线粒体中，加速了 gp120 诱导的细胞凋亡。这些数据表明，14-3-3τ 通过对 Bad 活性的负调节来防止 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 HBMEC（BBB 的主要细胞成分）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 BBB 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（例如 gp120 和 Tat）会增加内皮通透性，从而促进 HIV-1 穿过 BBB。我们发现，作为微血管通透性增加的新解释，gp120 会诱导 HBMEC 中蛋白酶体降解 TJ 蛋白，例如 ZO-1 和 ZO-2，并且 14-3-3τ 负向调节此过程。这些数据是证明 gp120 分解 BBB 的分子特性的第一个证据。较少的

项目成果

The Ubiquitin Proteasome System In Central Nervous System : From Physiology To Pathology" Edited by MD Napoli, JN. Keller, C Wojcik.

中枢神经系统中的泛素蛋白酶体系统：从生理学到病理学”由 MD Napoli、JN. Keller、C Wojcik 编辑。

• 发表时间: 2006
• 作者: Muraoka M;Hasegawa H et al.;Mihiro Yano
• 通讯作者: Mihiro Yano

Chaperone Activities of the 26S and 20S Proteasome.

26S 和 20S 蛋白酶体的伴侣活性。

• 发表时间: 2005
• 期刊: Current Protein ＆ Peptide Science 6
• 作者: Yamashita T;Arai K;Honda M et al.;Mihiro Yano;Nakashima Y;Hasegawa H et al.;Mihiro Yano.
• 通讯作者: Mihiro Yano.

The Ubiquitin Proteasome System In Central Nervous System : From Physiology To Pathology (Edited MD Napoli, JN Keller, C Wojcik)

中枢神经系统中的泛素蛋白酶体系统：从生理学到病理学（MD Napoli、JN Keller、C Wojcik 编辑）

• 发表时间: 2007
• 作者: Shimakami T;Honda M;Kusakawa T et al.;Hasegawa H et al.;Mihiro Yano
• 通讯作者: Mihiro Yano

Gatekeeper role of 14-3-3τ protein in HIV-1 gp120-mediated apoptosis of human endothelial cells by inactivation of Bad

14-3-3τ蛋白在HIV-1 gp120介导的Bad失活介导的人内皮细胞凋亡中的守门人作用

• 发表时间: 2007
• 期刊: AIDS 21(印刷中)
• 作者: Hiraga N;Imamura M;Tsuge M;Noguchi C;Takahashi S;Iwao E;Fujimoto Y;Abe H;Maekawa T;Ochi H;Tateno C;Yoshizato K;Sakai A;Sakai Y;Honda M;Kaneko S;Wakita T;Chayama K.;Mihiro Yano
• 通讯作者: Mihiro Yano

Chaperon Activities of the 26S and 20S Proteasome

26S 和 20S 蛋白酶体的伴侣活性

• 发表时间: 2005
• 期刊: Current Protein & Peptide Science. 6
• 作者: Sunagozaka H;Tsuji H;Honda M et al.;Suehiro Y;Mihiro Yano
• 通讯作者: Mihiro Yano