Human immunodeficiency virus type 1 gp120-mediated disruption of tight junction proteins by induction of proteasome-mediated degradation of zonula occludens-1 and-2 in human brain microvascular endothelial cells
Human immunodeficiency virus type 1 gp120-mediated disruption of tight junction proteins by induction of proteasome-mediated degradation of zonula occludens-1 and-2 in human brain microvascular endothelial cells
复制标题
DOI：
10.1080/13550280801993630
复制
发表时间：
2008-01-01
影响因子：
3.2
通讯作者：
Kido, Hiroshi
中科院分区：
文献类型：
--
作者：
Nakamuta, Shinichi;Endo, Hiroshi;Kido, Hiroshi
人类免疫缺陷病毒（HIV）-1（如HIV感染的白细胞）渗透穿过受损的血脑屏障（BBB）是HIV-1相关性痴呆的特征性病理表现。HIV-1 gp 120被认为是BBB内皮细胞之间紧密连接破坏的原因，尽管破坏的分子机制尚不清楚。该研究为BBB微血管通透性增加提供了新的解释，这是由于gp 120诱导的蛋白酶体降解紧密连接蛋白，以及支架蛋白14-3-3 tau gp 120对这一过程的负调控，减少了人脑微血管内皮细胞（HBMEC）中封闭小带（ZO）-1和ZO-2的数量。用蛋白酶体抑制剂lactacystin处理HBMEC，阻断ZO-1和ZO-2的降解，表明这些蛋白质被gp 120靶向用于蛋白酶体降解。gp 120还特异性地增加HBMEC中14-3-3 tau的表达，并且其通过RNAi的下调促进gp 120诱导的紧密连接蛋白的破坏。我们的研究结果证明了gp 120破坏血脑屏障的新分子机制。
The infiltration of human immunodeficiency virus (HIV)-1, such as by HIV-infected leukocytes, across an injured blood-brain barrier (BBB) is a characteristic pathologic manifestation of HIV-1-associated dementia. HIV-1 gp120 has been implicated as a cause of breakdown of tight junctions between endothelial cells of the BBB, though the disrupting molecular mechanisms are unexplained. This study offers a new explanation for the increased BBB microvascular permeability, due to the degradation of tight junction proteins by the proteasome induced by gp120, and the negative regulation of this process by the scaffold protein, 14-3-3 tau gp120 reduced the amount of zonula occludens (ZO)-1 and ZO-2 in human brain microvascular endothelial cells (HBMECs). The treatment of HBMECs with the proteasome inhibitor, lactacystin, blocked the degradation of ZO-1 and ZO-2, suggesting that these proteins were targeted by gp120 for degradation by the proteasome. gp120 also specifically increased the expression of 14-3-3 tau in HBMECs, and its down-regulation by RNAi facilitated the breakdown of tight junction proteins induced by gp120. Our results demonstrate the novel molecular mechanisms of the BBB breakdown by gp120.