Boon Siaw Shi, Tomaić Vjekoslav, Thomas Miranda, Roberts Sally, Banks Lawrence
International Centre for Genetic Engineering and Biotechnology, Trieste, Italy.
School of Cancer Sciences, University of Birmingham, Birmingham, United Kingdom.
J Virol. 2015 Feb;89(3):1579-86. doi: 10.1128/JVI.01961-14. Epub 2014 Nov 19.
Previous studies have shown that the cancer-causing high-risk human papillomavirus (HPV) E6 oncoproteins have PDZ binding potential, an activity which is important for their ability to support the viral life cycle and to cooperate in the induction of malignancy. However, PDZ interactions are not constitutive, and they can be negatively regulated by phosphorylation within the E6 PDZ binding motif (PBM). In this study, we have investigated the differential regulation of the HPV E6 PBMs from diverse high-risk HPV types. We show that, depending on the HPV type, PDZ binding activity can be regulated by phosphorylation with protein kinase A (PKA) or AKT, which, in turn, inhibits PDZ recognition. Such regulation is highly conserved between E6 proteins derived from HPV-16, HPV-18, and HPV-58 while being somewhat weaker or absent from other types such as HPV-31, HPV-33, and HPV-51. In the case of HPV31, PKA phosphorylation occurs within the core of the E6 protein and has no effect on PDZ interactions, and this demonstrates a surprising degree of heterogeneity among the different high-risk HPV E6 oncoproteins in how they are regulated by different cellular signaling pathways.
This study demonstrated that the cancer-causing HPV E6 oncoproteins are all subject to posttranslational modification of their extreme C-terminal PDZ binding motifs through phosphorylation. However, the identities of the kinase are not the same for all HPV types. This demonstrates a very important divergence between these HPVs, and it suggests that changes in cell signaling pathways have different consequences for different high-risk virus infections and their associated malignancies.
先前的研究表明，致癌的高危型人乳头瘤病毒（HPV）E6癌蛋白具有PDZ结合潜能，这一活性对于其支持病毒生命周期及协同诱导恶性肿瘤的能力而言至关重要。然而，PDZ相互作用并非是组成性的，它们可被E6的PDZ结合基序（PBM）内的磷酸化负调控。在本研究中，我们调查了来自不同高危型HPV的E6 PBM的差异调控。我们发现，取决于HPV类型，PDZ结合活性可被蛋白激酶A（PKA）或AKT磷酸化调控，这进而抑制了PDZ识别。这种调控在源自HPV-16、HPV-18和HPV-58的E6蛋白之间高度保守，而在其他类型如HPV-31、HPV-33和HPV-51中则较弱或不存在。就HPV31而言，PKA磷酸化发生在E6蛋白的核心区域，且对PDZ相互作用无影响，这表明不同高危型HPV E6癌蛋白在如何被不同细胞信号通路调控方面存在惊人程度的异质性。
本研究表明，致癌性HPV E6癌蛋白均通过磷酸化对其极端C末端PDZ结合基序进行翻译后修饰。然而，并非所有HPV类型的激酶都相同。这表明这些HPV之间存在非常重要的差异，并且表明细胞信号通路的变化对于不同高危病毒感染及其相关恶性肿瘤具有不同的后果。
