KSHV VIRF3 3 STABILIZES HIF1ALPHA TO INDUCE VEGF EXPRESSION

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 Kaposi肉瘤相关疱疹病毒(KSHV)是引起Kaposi肉瘤、原发性渗出性淋巴瘤和多中心Castleman病的病原体。缺氧诱导因子-1(HIF-1)是发育和病理性血管生成的主要调节因子，由氧敏感的α亚基和结构性表达的β亚基组成。HIF-1在肿瘤中的活性取决于HIF-1α亚基的可用性，在低氧条件下，HIF-1α亚基的水平会增加。最近的研究表明，HIF-1在KSHV的潜伏期和发病机制中起着重要的作用。在此，我们报道了KSHV激活HIF-1活性的一种新机制。KSHV病毒干扰素调节因子3(VIRF3)与HIF-1α亚基的特异性相互作用导致HIF-1α的稳定和转录激活，从而诱导血管内皮生长因子的表达，最终促进血管内皮细胞的形成。值得注意的是，vIRF3的中心结构域包含两个α-螺旋基序，不仅足以与HIF-1α结合，而且足以阻止其在常氧条件下的降解。与艾滋病有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent associated with Kaposi's sarcoma, primary effusion lymphoma, and multicentric Castleman's disease. Hypoxia inducible factor 1 (HIF-1) is the master regulator of both developmental and pathological angiogenesis, composed of an oxygen-sensitive alpha-subunit and a constitutively expressed beta-subunit. HIF-1 activity in tumors depends on the availability of the HIF-1alpha subunit, the levels of which are increased under hypoxic conditions. Recent studies have shown that HIF-1 plays an important role in KSHV reactivation from latency and pathogenesis. Here, we report a novel mechanism by which KSHV activates HIF-1 activity. Specific interaction between KSHV viral interferon regulatory factor 3 (vIRF3) and the HIF-1alpha subunit led to the HIF-1alpha stabilization and transcriptional activation, which induced VEGF expression and ultimately facilitated endothelial tube formation. Remarkably, the central domain of vIRF3, containing double alpha-helix motifs, was sufficient not only for binding to HIF-1alpha, but also for blocking its degradation in normoxic conditions. AIDS related.