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），也被称为人类疱疹病毒8 (HHV-8)，是卡波西肉瘤（KS）和两种淋巴细胞恶性肿瘤的病原体。疱疹病毒进入细胞是一个涉及多种病毒糖蛋白和细胞受体的多步骤过程。最近，我们发现了KSHV糖蛋白H和L （gH/gL）的第一个受体：Ephrin受体-酪氨酸激酶A2 （EphA2）。EphA2对于内皮细胞的感染是至关重要的，如果不是绝对必要的，内皮细胞是KS的起源。EphA2不仅是KSHV的受体；它也被认为有助于肿瘤的发生和新血管的形成。其中，EphA2与分子相互作用并触发已知参与KSHV进入的信号级联反应。EphA2在许多实体肿瘤中高表达。我们在KS中也证明了这一点。有趣的是，虽然EphA2在潜伏KSHV感染的KS组织中上调，但KSHV裂解复制的再激活伴随着EphA2表达的显著降低。EphA2表达调控的机制尚不清楚。我们发现KSHV转录因子RTA足以在KSHV再激活时下调EphA2。综上所述，EphA2可能是KSHV感染中参与KS发病的关键分子。然而，到目前为止，EphA2参与的KSHV进入的步骤还没有明确定义。确定进入过程中受EphA2、2调控的步骤。EphA2在KSHV进入/感染中的胞内结构域解剖，2。EphA2触发的与KSHV进入相关的信号通路的鉴定。4. RTA调控EphA2表达的机制（转录或转录后）鉴定。分析EphA2参与KSHV的进入和KSHV对其的调控不仅对了解KSHV的生物学和KS的发病机制有重要意义，而且还将揭示EphA2在癌症中的一般功能。

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.