The role of Ephrin-A2 receptor-tyrosinkinase in Kaposi sarcoma-associated herpesvirus infection

卡波西肉瘤相关疱疹病毒(KSHV)，又称人类疱疹病毒8型(HHV-8)，是卡波西肉瘤(KS)和两种淋巴系统恶性肿瘤的病原体。疱疹病毒进入细胞是一个多步骤的过程，涉及几种病毒糖蛋白和细胞受体。最近，我们发现了KSHV糖蛋白H和L(Gh/Gl)的第一个受体：EphA2受体-酪氨酸激酶A2。EphA2对于内皮细胞的感染是至关重要的，而内皮细胞是KS的来源。EphA2不仅是KSHV的受体，它还有助于肿瘤的发生和新生血管的形成。其中，EphA2与分子相互作用，触发已知参与KSHV进入的信号级联反应。EphA2在许多实体肿瘤中高表达。我们证明了在KS中也是如此。有趣的是，虽然EphA2在潜伏感染KSHV的KS组织中上调，但KSHV裂解复制的重新激活伴随着EphA2表达的显著降低。EphA2表达调控的机制(S)基本上是未知的。我们证明了KSHV转录因子RTA足以在KSHV重新激活时下调EphA2。综上所述，EphA2可能是KSHV感染的关键分子，参与了KS的发病过程。然而，到目前为止，EphA2参与的KSHV进入KSHV的步骤(S)还没有得到很好的确定。本项目的目标是：1.识别EphA2调控的进入过程中的步骤；2.解剖KSHV进入/感染过程中EphA2的胞内结构域；3.确定EphA2触发的与KSHV进入相关的信号通路。4.鉴定RTA对EphA2表达的转录或转录后调控机制。因此，分析EphA2在KSHV进入KSHV过程中的作用以及KSHV对EphA2的调控作用，不仅对了解KSHV的生物学特性和KS的发病机制具有重要意义，而且对于揭示EphA2在肿瘤中的作用也具有重要意义。

Kaposi sarcoma-associated herpesvirus (KSHV), also termed human herpesvirus 8 (HHV-8), is the causative agent of Kaposi sarcoma (KS) and two lymphoid malignancies. Entry of a herpesvirus into a cell is a multi-step process involving several viral glycoproteins and cellular receptors. Recently, we identified the first receptor for KSHV glycoprotein H and L (gH/gL): Ephrin receptor-tyrosinkinase A2 (EphA2). EphA2 is crucial if not absolutely essential for the infection of endothelial cells which are the origin of KS. EphA2 is not only a receptor for KSHV; it is also known to contribute to oncogenesis and neo-vascularization. Amongst others, EphA2 interacts with molecules and triggers signaling cascades that are known to be involved in KSHV entry. EphA2 is highly expressed in many solid tumors. We showed that this is the case in KS, too. Interestingly, whereas EphA2 is upregulated in latently KSHV infected KS tissues, reactivation of KSHV lytic replication is accompanied by a marked reduction of EphA2 expression. The mechanism(s) of EphA2 expression regulation are essentially unknown. We showed that the KSHV transcription factor RTA is sufficient for EphA2 downregulation upon KSHV reactivation. In summary, EphA2 is likely to be a key molecule in KSHV infection that contributes to KS pathogenesis. However, the step(s) of KSHV entry in which EphA2 is involved have been poorly defined so far The goals of this project are: 1. Identification of the steps in the entry process that are regulated by EphA2, 2. Dissection of the intracellular domains of EphA2 involved in KSHV entry/infection, 3. identification of the signaling pathways triggered by EphA2 which are relevant for KSHV entry. 4. Identification of the mechanisms (transcriptional or post-transcriptional) of EphA2 expression-regulation by RTA. It is likely that the analysis of EphA2 involvement in KSHV entry and its regulation by KSHV will not only be important for the understanding of KSHV biology and KS pathogenesis but will also shed light on the functions of EphA2 in cancer in general.