Inhibition of Non Canonical HIV-1 Tat Secretion Through the Cellular Na(+),K(+)-ATPase Blocks HIV-1 Infection.
Inhibition of Non Canonical HIV-1 Tat Secretion Through the Cellular Na(+),K(+)-ATPase Blocks HIV-1 Infection.
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DOI：
10.1016/j.ebiom.2017.06.011
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发表时间：
2017-07
期刊：
影响因子：
11.1
通讯作者：
Giacca M
中科院分区：
文献类型：
--
作者：
Agostini S;Ali H;Vardabasso C;Fittipaldi A;Tasciotti E;Cereseto A;Bugatti A;Rusnati M;Lusic M;Giacca M
除了在HIV-1基因表达的激活中起重要作用外，病毒达特蛋白还具有进出细胞的不寻常特性。与达特内化相反，涉及细胞外达特释放的机制迄今为止仍然难以捉摸。在这里，我们表明，达特分泌发生通过高尔基体独立的途径，需要结合达特与三个短的，非连续的胞浆内循环在C-末端的细胞Na+，K+-ATP酶泵α亚基。哇巴因，一种泵抑制剂，阻断了这种相互作用，并阻止了达特分泌;在这种药物存在下产生的病毒粒子的感染性较低，与病毒粒子相关的达特增加HIV-1感染性的能力一致。用与泵α亚基的Tat结合区相对应的短肽处理CD 4 + T细胞会损害细胞外达特释放并阻断HIV-1复制。因此，非典型的细胞外达特分泌是病毒感染性所必需的。HIV-1达特的细胞外分泌由细胞Na+ K+-ATP酶泵介导。达特释放被Na+ K+-ATP酶抑制剂哇巴因抑制。哇巴因肽与ATP酶上的达特对接位点竞争，阻断达特分泌。通过阻断细胞外达特释放产生的HIV-1病毒粒子的感染性较低。HIV-1的达特蛋白是病毒基因表达的重要调节因子。除了在细胞核中的这种作用外，我们还发现这种蛋白质通过与细胞膜Na+ K+ ATP酶蛋白亚基结合的机制分泌到细胞外。用阻断这种相互作用的肽处理细胞可防止达特释放，因此，显著降低HIV-1病毒粒子的感染性。这些发现可能为开发创新药物铺平道路，通过阻断Tat-ATPase相互作用，阻断HIV-1感染。
Besides its essential role in the activation of HIV-1 gene expression, the viral Tat protein has the unusual property of trafficking in and out of cells. In contrast to Tat internalization, the mechanism involved in extracellular Tat release has so far remained elusive. Here we show that Tat secretion occurs through a Golgi-independent pathway requiring binding of Tat with three short, non-consecutive intracytoplasmic loops at the C-terminus of the cellular Na+,K+-ATPase pump alpha subunit. Ouabain, a pump inhibitor, blocked this interaction and prevented Tat secretion; virions produced in the presence of this drug were less infectious, consistent the capacity of virion-associated Tat to increase HIV-1 infectivity. Treatment of CD4 + T-cells with short peptides corresponding to the Tat-binding regions of the pump alpha subunit impaired extracellular Tat release and blocked HIV-1 replication. Thus, non canonical, extracellular Tat secretion is essential for viral infectivity. Extracellular secretion of HIV-1 Tat is mediated by the cellular Na+ K+-ATPase pump. Tat release is inhibited by the Na+ K+-ATPase inhibitor ouabain Peptides competing with the Tat docking site on the ATPase block Tat secretion. HIV-1 virions produced by blocking extracellular Tat release are less infectious. The Tat protein of HIV-1 is an essential regulator of viral gene expression. In addition to this role in the nucleus, here we show that this protein is secreted outside the cells through a mechanism involving its binding to a subunit of the cell membrane Na+ K+ ATPase protein. Cell treatment with peptides blocking this interaction prevents Tat release and, as a consequence, markedly diminishes infectivity of HIV-1 virions. These findings might pave the way to the development of innovative drugs that, by blocking the Tat-ATPase interaction, block HIV-1 infection.
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DOI：
10.1073/pnas.82.10.3197
发表时间：
1985-01-01
影响因子：
11.1
作者：
ESKO, JD;STEWART, TE;TAYLOR, WH
通讯作者：
TAYLOR, WH
影响因子：
4.9
作者：
Ewart, GD;Nasr, N;Gage, PW
通讯作者：
Gage, PW
影响因子：
82.9
作者：
Manganaro, Lara;Lusic, Marina;Giacca, Mauro
通讯作者：
Giacca, Mauro
影响因子：
64.5
作者：
BERKHOUT, B;SILVERMAN, RH;JEANG, KT
通讯作者：
JEANG, KT
影响因子：
4.8
作者：
Becker-Hapak, M;McAllister, SS;Dowdy, SF
通讯作者：
Dowdy, SF