Graduate Institute of Microbiology, College of Medicine, National Taiwan University , Taipei, Taiwan.
Department of Biochemical Science and Technology, National Taiwan University , Taipei, Taiwan.
J Virol. 2023 Aug 31;97(8):e0054023. doi: 10.1128/jvi.00540-23. Epub 2023 Jul 28.
Epstein-Barr virus (EBV) is a human oncogenic γ-herpesvirus that establishes persistent infection in more than 90% of the world's population. EBV has two life cycles, latency and lytic replication. Reactivation of EBV from latency to the lytic cycle is initiated and controlled by two viral immediate-early transcription factors, Zta and Rta, encoded by and , respectively. In this study, we found that IQGAP2 expression was elevated in EBV-infected B cells and identified Rta as a viral gene responsible for the IQGAP2 upregulation in both B cells and nasopharyngeal carcinoma cell lines. Mechanistically, we showed that Rta increases IQGAP2 expression through direct binding to the Rta-responsive element in the IQGAP2 promoter. We also demonstrated the direct interaction between Rta and IQGAP2 as well as their colocalization in the nucleus. Functionally, we showed that the induced IQGAP2 is required for the Rta-mediated Rta promoter activation in the EBV lytic cycle progression and may influence lymphoblastoid cell line clumping morphology through regulating E-cadherin expression. IMPORTANCE Elevated levels of antibodies against EBV lytic proteins and increased EBV DNA copy numbers in the sera have been reported in patients suffering from Burkitt's lymphoma, Hodgkin's lymphoma, and nasopharyngeal carcinoma, indicating that EBV lytic cycle progression may play an important role in the pathogenesis of EBV-associated diseases and highlighting the need for a more complete mechanistic understanding of the EBV lytic cycle. Rta acts as an essential transcriptional activator to induce lytic gene expression and thus trigger EBV reactivation. In this study, scaffolding protein IQGAP2 was found to be upregulated prominently following EBV infection via the direct binding of Rta to the RRE in the IQGAP2 promoter but not in response to other biological stimuli. Importantly, IQGAP2 was demonstrated to interact with Rta and promote the EBV lytic cycle progression. Suppression of IQGAP2 was also found to decrease E-cadherin expression and affect the clumping morphology of lymphoblastoid cell lines.
EB 病毒（EBV）是一种人类致癌γ疱疹病毒，它在世界上超过 90%的人口中建立持续性感染。EBV 有两种生命周期，潜伏期和裂解复制。EBV 从潜伏状态到裂解周期的再激活是由两个病毒即刻早期转录因子 Zta 和 Rta 启动和控制的，分别由 和 编码。在这项研究中，我们发现 IQGAP2 在 EBV 感染的 B 细胞中表达上调，并确定 Rta 是负责 B 细胞和鼻咽癌细胞系中 IQGAP2 上调的病毒基因。在机制上，我们表明 Rta 通过直接结合 IQGAP2 启动子中的 Rta 反应元件来增加 IQGAP2 的表达。我们还证明了 Rta 和 IQGAP2 之间的直接相互作用以及它们在核内的共定位。功能上，我们表明诱导的 IQGAP2 是 Rta 介导的 EBV 裂解周期进展中 Rta 启动子激活所必需的，并且可能通过调节 E-钙粘蛋白表达来影响淋巴母细胞系聚集形态。重要性 据报道，患有 Burkitt 淋巴瘤、霍奇金淋巴瘤和鼻咽癌的患者血清中针对 EBV 裂解蛋白的抗体水平升高和 EBV DNA 拷贝数增加，这表明 EBV 裂解周期的进展可能在 EBV 相关疾病的发病机制中起重要作用，并强调需要更全面地了解 EBV 裂解周期的机制。Rta 作为一种必需的转录激活因子，诱导裂解基因表达，从而触发 EBV 再激活。在这项研究中，发现支架蛋白 IQGAP2 在 EBV 感染后通过 Rta 直接结合 IQGAP2 启动子中的 RRE 而不是响应其他生物刺激而显著上调。重要的是，已经证明 IQGAP2 与 Rta 相互作用并促进 EBV 裂解周期的进展。IQGAP2 的抑制也发现会降低 E-钙粘蛋白的表达并影响淋巴母细胞系的聚集形态。
