Opposite effects of HIV-1 p17 variants on PTEN activation and cell growth in B cells.
Opposite effects of HIV-1 p17 variants on PTEN activation and cell growth in B cells.
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DOI：
10.1371/journal.pone.0017831
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发表时间：
2011-03-14
期刊：
影响因子：
3.7
通讯作者：
Caruso A
中科院分区：
文献类型：
--
作者：
Giagulli C;Marsico S;Magiera AK;Bruno R;Caccuri F;Barone I;Fiorentini S;Andò S;Caruso A
HIV-1基质蛋白p17是一种结构蛋白，可在细胞外环境中通过其NH 2-末端区域与细胞表面受体（p17 R）的相互作用来解除免疫细胞的几种功能。由p17/p17 R相互作用触发的细胞内事件尚未完全表征。在这项研究中，我们分析了p17/p17 R相互作用诱导的信号转导途径，并表明，在Raji细胞，人B细胞系稳定表达p17 R在其表面上，p17诱导转录因子AP-1的瞬时激活。此外，它被发现上调pERK 1/2和下调pAkt，这是参与AP-1激活的主要细胞内信号传导组分。这些作用是由p17的COOH末端区域介导的，该区域显示出通过丝氨酸/苏氨酸（Ser/Thr）激酶ROCK保持PTEN（一种调节PI 3 K/Akt通路的磷酸酶）处于活性状态的能力。事实上，COOH末端截短形式的p17（p17Δ36）通过维持PTEN处于失活的磷酸化形式来诱导PI 3 K/Akt途径的激活。有趣的是，我们发现在不同的p17中，来自乌干达HIV-1株的变体S75 X触发了PI 3 K/Akt信号通路的激活，并导致B细胞增殖和恶性转化增加。总之，本研究显示了COOH末端区域在调节p17信号通路中的作用，因此突出了p17与其受体结合并通过其受体进行信号传导的复杂性。此外，它提供了关于p17天然变体存在的第一个证据，该天然变体模拟B细胞中p17Δ36诱导的信号传导，并显示出促进B细胞生长和肿瘤发生的能力。
The HIV-1 matrix protein p17 is a structural protein that can act in the extracellular environment to deregulate several functions of immune cells, through the interaction of its NH2-terminal region with a cellular surface receptor (p17R). The intracellular events triggered by p17/p17R interaction have been not completely characterized yet. In this study we analyze the signal transduction pathways induced by p17/p17R interaction and show that in Raji cells, a human B cell line stably expressing p17R on its surface, p17 induces a transient activation of the transcriptional factor AP-1. Moreover, it was found to upregulate pERK1/2 and downregulate pAkt, which are the major intracellular signalling components involved in AP-1 activation. These effects are mediated by the COOH-terminal region of p17, which displays the capability of keeping PTEN, a phosphatase that regulates the PI3K/Akt pathway, in an active state through the serin/threonin (Ser/Thr) kinase ROCK. Indeed, the COOH-terminal truncated form of p17 (p17Δ36) induced activation of the PI3K/Akt pathway by maintaining PTEN in an inactive phosphorylated form. Interestingly, we show that among different p17s, a variant derived from a Ugandan HIV-1 strain, named S75X, triggers an activation of PI3K/Akt signalling pathway, and leads to an increased B cell proliferation and malignant transformation. In summary, this study shows the role of the COOH-terminal region in modulating the p17 signalling pathways so highlighting the complexity of p17 binding to and signalling through its receptor(s). Moreover, it provides the first evidence on the presence of a p17 natural variant mimicking the p17Δ36-induced signalling in B cells and displaying the capacity of promoting B cell growth and tumorigenesis.
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