Dalton-Griffin Lucy, Wilson Sam J, Kellam Paul
Department of Infection, UCL, London, United Kingdom.
J Virol. 2009 Jul;83(14):7202-9. doi: 10.1128/JVI.00076-09. Epub 2009 Apr 29.
Kaposi's sarcoma-associated herpesvirus (KSHV), like other herpesviruses, has two stages to its life cycle: latency and lytic replication. KSHV is required for development of Kaposi's sarcoma, a tumor of endothelial origin, and is associated with the B-cell tumor primary effusion lymphoma (PEL) and the plasmablastic variant of multicentric Castleman's disease, all of which are characterized by predominantly latent KSHV infection. Recently, we and others have shown that the activated form of transcription factor X-box binding protein 1 (XBP-1) is a physiological trigger of KSHV lytic reactivation in PEL. Here, we show that XBP-1s transactivates the ORF50/RTA promoter though an ACGT core containing the XBP-1 response element, an element previously identified as a weakly active hypoxia response element (HRE). Hypoxia induces the KSHV lytic cycle, and active HREs that respond to hypoxia-inducible factor 1alpha are present in the ORF50/RTA promoter. Hypoxia also induces active XBP-1s, and here, we show that both transcription factors contribute to the induction of RTA expression, leading to the production of infectious KSHV under hypoxic conditions.
卡波西肉瘤相关疱疹病毒（KSHV）与其他疱疹病毒一样，其生命周期有两个阶段：潜伏期和裂解复制期。KSHV是内皮起源的肿瘤——卡波西肉瘤发生所必需的，并且与B细胞肿瘤原发性渗出性淋巴瘤（PEL）以及多中心Castleman病的浆母细胞变异型有关，所有这些疾病的特征均主要为KSHV潜伏感染。最近，我们和其他人已表明，转录因子X盒结合蛋白1（XBP-1）的激活形式是PEL中KSHV裂解再激活的生理触发因素。在此，我们表明XBP-1s通过一个包含XBP-1反应元件的ACGT核心来反式激活ORF50/RTA启动子，该元件先前被鉴定为一个弱活性缺氧反应元件（HRE）。缺氧诱导KSHV裂解周期，并且在ORF50/RTA启动子中存在对缺氧诱导因子1α有反应的活性HRE。缺氧还诱导活性XBP-1s，并且在此我们表明这两种转录因子均有助于RTA表达的诱导，从而导致在缺氧条件下产生有感染性的KSHV。
