HIV-1 nef assembles a src family Kinase-ZAP-70/Syk-PI3K cascade to downregulate cell-surface MHC-I
HIV-1 nef assembles a src family Kinase-ZAP-70/Syk-PI3K cascade to downregulate cell-surface MHC-I
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DOI：
10.1016/j.chom.2007.03.004
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发表时间：
2007-04-01
影响因子：
30.3
通讯作者：
Thomas, Gary
中科院分区：
文献类型：
--
作者：
Hung, Chien-Hui;Thomas, Laurel;Thomas, Gary
HIV-1 Nef是艾滋病有效发病所必需的，它通过对受感染细胞施加多种作用来增强病毒复制和传染性。NEF通过一个未知的PI3K途径下调细胞表面的MHC-I分子，需要两个Nef基序-EE65和PXXP75的作用。我们报道，Nef EE65靶向基序使Nef PXXP75能够结合并激活反式高尔基体网络定位的Src家族酪氨酸激酶(SFK)。然后，Nef/SFK复合体招募并磷酸化酪氨酸激酶ZAP-70，ZAP-70与I类PI3K结合，触发初级CD4(+)T细胞中MHC-I的下调。在原单核细胞中，Nef/SFK招募ZAP-70同源Syk下调MHC-1，在多个HIV-1储存库中涉及PI3K途径。异构体特异性的PI3K抑制剂抑制MHC-I的下调，确定它们是对抗HIV-1的潜在治疗剂。Nef-SFK-ZAP-70/Syk-PI3K信号通路的发现解释了Nef基序在免疫逃避中的层次性作用。
HIV-1 Nef, which is required for the efficient onset of AIDS, enhances viral replication and infectivity by exerting multiple effects on infected cells. Nef downregulates cell-surface MHC-I molecules by an uncharacterized PI3K pathway requiring the actions of two Nef motifs-EEEE65 and PXXP75. We report that the Nef EEEE65 targeting motif enables Nef PXXP75 to bind and activate a trans-Golgi network-localized Src family tyrosine kinase (SFK). The Nef/SFK complex then recruits and phosphorylates the tyrosine kinase ZAP-70, which binds class I PI3K to trigger MHC-I downregulation in primary CD4(+) T cells. In promonocytic cells, Nef/SFK recruits the ZAP-70 homolog Syk to downregulate MHC-1, implicating this PI3K pathway in multiple HIV-1 reservoirs. Isoform-specific PI3K inhibitors repress MHC-I downregulation, identifying them as potential therapeutic agents to combat HIV-1. The discovery of this Nef-SFK-ZAP-70/ Syk-PI3K signaling pathway explains the hierarchal role of the Nef motifs in effecting immunoevasion.