Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor
Interaction between Hck and HIV-1 Nef negatively regulates cell surface expression of M-CSF receptor
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DOI：
10.1182/blood-2007-04-086017
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发表时间：
2008-01-01
期刊：
影响因子：
20.3
通讯作者：
Okada, Seiji
中科院分区：
文献类型：
--
作者：
Hiyoshi, Masateru;Suzu, Shinya;Okada, Seiji
Nef是HIV-1的一种多功能致病蛋白，它与Hck（一种在巨噬细胞中高表达的Src酪氨酸激酶）的相互作用已被证明与AIDS的发展有关。然而，Nef-Hck相互作用如何导致巨噬细胞的功能异常知之甚少。我们最近发现Nef显着抑制巨噬细胞集落刺激因子（M-CSF）的活性，M-CSF是巨噬细胞的主要细胞因子。在这里，我们表明，Nef的抑制作用是由于HCK依赖性下调M-CSF受体Fms的细胞表面表达。在Hck的存在下，Nef诱导积累的未成熟的N-糖基化的Fms在高尔基体，从而下调Fms。Hck与Nef的直接相互作用激活Hck是下调Hck表达的必要条件。出乎意料的是，聚集在高尔基体的活性Hck，其中Nef预定位可能是另一个关键的决定因素Nef的功能，因为表达的组成型活性形式的Hck单独没有完全下调Fms。这些结果表明，Nef干扰细胞内的成熟和运输的新生Fms，通过一个独特的机制，需要激活的Hck和异常的空间调节的活性Hck。
Nef is a multifunctional pathogenetic protein of HIV-1, the interaction of which with Hck, a Src tyrosine kinase highly expressed in macrophages, has been shown to be responsible for the development of AIDS. However, how the Nef-Hck interaction leads to the functional aberration of macrophages is poorly understood. We recently showed that Nef markedly inhibited the activity of macrophage colony-stimulating factor (M-CSF), a primary cytokine for macrophages. Here, we show that the inhibitory effect of Nef is due to the Hck-dependent down-regulation of the cell surface expression of M-CSF receptor Fms. In the presence of Hck, Nef induced the accumulation of an immature under-N-glycosylated Fms at the Golgi, thereby down-regulating Fms. The activation of Hck by the direct interaction with Nef was indispensable for the down-regulation. Unexpectedly, the accumulation of the active Hck at the Golgi where Nef prelocalized was likely to be another critical determinant of the function of Nef, because the expression of the constitutive-active forms of Hck alone did not fully down-regulate Fms. These results suggest that Nef perturbs the intracellular maturation and the trafficking of nascent Fms, through a unique mechanism that required both the activation of Hck and the aberrant spatial regulation of the active Hck.