HIV-1 Nef promotes survival of myeloid cells by a stat3-dependent pathway
HIV-1 Nef promotes survival of myeloid cells by a stat3-dependent pathway
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DOI：
10.1074/jbc.m103244200
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发表时间：
2001-07-06
影响因子：
4.8
通讯作者：
Smithgall, TE
中科院分区：
文献类型：
--
作者：
Briggs, SD;Scholtz, B;Smithgall, TE
人类免疫缺陷病毒Nef是一种在艾滋病进展中起关键作用的小豆蔻酰化蛋白。Nef在体外与骨髓限制性酪氨酸激酶Hck的SH 3结构域以高亲和力结合，将此Src相关激酶鉴定为Nef在巨噬细胞中的可能细胞靶点。在这里，我们表明，Nef激活内源性HCK的粒细胞-巨噬细胞集落刺激因子依赖性骨髓细胞系，TF-1。出乎意料的是，Nef诱导了不依赖于精氨酸的TF-1细胞生长和Stat 3转录因子的组成性激活。诱导生存需要的Nef SH 3结合和膜靶向图案，并被显性阴性Stat 3突变体阻断。Nef还刺激了原代人巨噬细胞中的Stat 3活化，为Stat 3作为人类免疫缺陷病毒靶细胞中的Nef效应子提供了证据。
Human immunodeficiency virus Nef is a small myristylated protein that plays a critical role in AIDS progression. Nef binds with high affinity to the SH3 domain of the myeloid-restricted tyrosine kinase Hck in vitro, identifying this Src-related kinase as a possible cellular target for Nef in macrophages. Here we show that Nef activates endogenous Hck in the granulocyte-macrophage colony-stimulating factor-dependent myeloid cell line, TF-1. Unexpectedly, Nef induced cytokine-independent TF-1 cell outgrowth and constitutive activation of the Stat3 transcription factor. Induction of survival required the Nef SH3 binding and membrane-targeting motifs and was blocked by dominant-negative Stat3 mutants. Nef also stimulated Stat3 activation in primary human macrophages, providing evidence for Stat3 as a Nef effector in a target cell for human immunodeficiency virus.