STP-C, an oncoprotein of Herpesvirus saimiri augments the activation of NF-κB through ubiquitination of TRAF6
STP-C, an oncoprotein of Herpesvirus saimiri augments the activation of NF-κB through ubiquitination of TRAF6
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DOI：
10.5483/bmbrep.2007.40.3.341
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发表时间：
2007-05-31
期刊：
影响因子：
--
通讯作者：
Lee, Sang Jun
中科院分区：
文献类型：
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作者：
Chung, Young-Hwa;Jhun, Byung Hak;Lee, Sang Jun
猴猴疱疹病毒（HVS）是γ -疱疹病毒家族的一员，它编码一种叫做猴猴转化蛋白（STP）的癌蛋白，这种蛋白是非人灵长类动物诱导淋巴瘤所必需的。先前的研究表明，RVS的癌蛋白STP-C可激活NF-KB信号通路。然而，stp - c介导的NF-KB活化的详细机制尚未报道。我们首先报道了STP-C在体内和体外与TRAF6蛋白相互作用，进一步的研究表明STP-C的Glu（12）残基是与TRAF6结合的关键。与单独表达STP-C相比，泛素和STP-C的引入增强了NF-KB的活性。STP-C表达进一步诱导内源性TRAF6泛素化。此外，尽管存在STP-C，去泛素化酶CYLD或显性负e2偶联酶都降低了NF-KB的活性，这表明STP-C与TRAF6的相互作用诱导了TRAF6的泛素化。STP-C通过泛素化的TRAF6激活NF-KB，导致炎症趋化因子IL-8的产生增加，共刺激分子ICAM的表达增强，这可能最终通过暴露于hvs感染的细胞炎症微环境和慢性激活来促进细胞转化。
Herpesvirus saimiri (HVS), a member of the gamma-herpesvirus family, encodes an oncoprotein called Saimiri Transforming Protein (STP) which is required for lymphoma induction in non-human primates. Previous study has shown that STP-C, an oncoprotein of RVS, activates NF-KB signaling pathway. However, the detailed mechanism of STP-C-mediated NF-KB activation has not been reported yet. We first report that STP-C interacts with TRAF6 protein in vivo and in vitro and further investigation shows that Glu(12) residue of STP-C is critical for binding to TRAF6. Introduction of ubiquitin together with STP-C augments NF-KB activity compared to that of STP-C expression alone. STP-C expression further induces ubiquitination of endogenous TRAF6. In addition, either a deubiquitination enzyme, CYLD or a dominant negative E2-conjugation enzyme reduced NF-KB activity in spite of the presence of STP-C, supporting that the interaction between STP-C and TRAF6 induces ubiquitination of TRAF6. NF-KB activation by STP-C through the ubiquitinated TRAF6 causes the increased production of IL-8, an inflammatory chemokine and the enhanced expression of costimulatory molecule ICAM, which might ultimately contribute cellular transformation by the exposure of HVS-infected cells with inflammatory microenvironment and chronic activation.