A potential α-helix motif in the amino terminus of LANA encoded by Kaposi's sarcoma-associated herpesvirus is critical for nuclear accumulation of HIF-1α in normoxia
A potential α-helix motif in the amino terminus of LANA encoded by Kaposi's sarcoma-associated herpesvirus is critical for nuclear accumulation of HIF-1α in normoxia
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DOI：
10.1128/jvi.00611-07
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发表时间：
2007-10-01
影响因子：
5.4
通讯作者：
Robertson, Erle S.
中科院分区：
文献类型：
--
作者：
Cai, Qiliang;Murakami, Masanao;Robertson, Erle S.
缺氧诱导因子1（HIF-1）是一种广泛表达的转录调节因子，参与诱导许多与血管生成和肿瘤生长相关的基因。卡波西肉瘤是一种高度血管化的内皮细胞源性肿瘤，与血管生成增加有关。以前，我们已经表明，由卡波西肉瘤相关疱疹病毒（KSHV）编码的潜伏相关核抗原（拉娜）靶向HIF-1 α抑制因子von Hippel-Lindau蛋白和p53，通过其细胞因子信号传导盒基序的抑制因子进行降解，该基序招募EC 5S泛素复合物。在此，我们进一步表明，HIF-1 α在KSHV潜伏感染的原发性渗出性淋巴瘤（PEL）细胞以及感染KSHV的HEK 293细胞中异常积累，并且还表明，在常氧条件下，潜在的拉娜α-螺旋氨基末端结构域对HIF-1 α核积累很重要。此外，我们现在已经确定这种关联依赖于拉娜的残基46至89和HIF-1 α的氧依赖性降解结构域。将针对拉娜的特异性小干扰RNA引入PEL细胞中也导致HIF-1 α的核积累减少。因此，这些数据表明，拉娜不仅可以作为HIF-1 α抑制蛋白的抑制剂发挥作用，而且还可以在KSHV潜伏感染期间诱导HIF-1 α的核积累。
Hypoxia-inducible factor 1 (HIF-1) is a ubiquitously expressed transcriptional regulator involved in induction of numerous genes associated with angiogenesis and tumor growth. Kaposi's sarcoma, associated with increased angiogenesis, is a highly vascularized, endothelial cell-derived tumor. Previously, we have shown that the latency-associated nuclear antigen (LANA) encoded by Kaposi's sarcoma-associated herpesvirus (KSHV) targets the HIF-1 alpha suppressors von Hippel-Lindau protein and p53 for degradation via its suppressor of cytokine signaling-box motif, which recruits the EC5S ubiquitin complex. Here we further show that HIF-1 alpha was aberrantly accumulated in KSHV latently infected primary effusion lymphoma (PEL) cells, as well as HEK293 cells infected with KSHV, and also show that a potential a-helical amino-terminal domain of LANA was important for HIF-1 alpha nuclear accumulation in normoxic conditions. Moreover, we have now determined that this association was dependent on the residues 46 to 89 of LANA and the oxygen-dependent degradation domain of HIF-1 alpha. Introduction of specific small interfering RNA against LANA into PEL cells also resulted in a diminished nuclear accumulation of HIF-1 alpha. Therefore, these data show that LANA can function not only as an inhibitor of HIF-1 alpha suppressor proteins but can also induce nuclear accumulation of HIF-1 alpha during KSHV latent infection.