Induction of Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral Interleukin-6 by X-Box Binding Protein 1
Induction of Kaposi's Sarcoma-Associated Herpesvirus-Encoded Viral Interleukin-6 by X-Box Binding Protein 1
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DOI：
10.1128/jvi.01192-15
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发表时间：
2016-01-01
影响因子：
5.4
通讯作者：
Yarchoan, Robert
中科院分区：
文献类型：
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作者：
Hu, Duosha;Wang, Victoria;Yarchoan, Robert
卡波西肉瘤相关疱疹病毒（KSHV）是卡波西肉瘤（KS）、原发性渗出性淋巴瘤（PEL）和多中心Castleman病（MCD）的一个子集的病原体。KSHV的生命周期有两个主要的基因库，潜伏和裂解。KSHV病毒白细胞介素-6（vIL-6）是人IL-6的一种类似物，通常是裂解性的;相关浆母细胞产生vIL-6是KSHV-MCD的主要特征。vIL-6也在PEL和KS中起作用。我们发现，KSHV-MCD患者淋巴结中的一些浆母细胞表达vIL-6，但不表达KSHV裂解基因ORF 45。我们进一步表明，vIL-6是直接诱导的剪接（活性）X-box结合蛋白-1（XBP-1 s），内质网（ER）应激和淋巴结中的B细胞分化激活的转录因子。vIL-6的启动子区含有几个潜在的XBP反应元件（XRE），其中两个元件特别介导XBP-1的作用。这些元件的突变消除了对XBP-1的反应，但不消除对KSHV复制和转录激活因子（RTA）的反应。此外，XBP-1 s在这些XRE的区域中与vIL-6启动子结合。将PEL细胞暴露于XBP-1的化学诱导剂可诱导vIL-6。产生vIL-6的患者源性PEL肿瘤细胞经常共表达XBP-1，并且涉及的KSHV-MCD淋巴结的免疫荧光染色显示，大多数表达vIL-6的浆母细胞也共表达XBP-1。这些结果提供了证据表明，XBP-1 s是KSHV vIL-6的直接激活剂，这是KSHV-MCD和PEL发病机制中的重要步骤。
Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent for Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and a subset of multicentric Castleman disease (MCD). The KSHV life cycle has two principal gene repertoires, latent and lytic. KSHV viral interleukin-6 (vIL-6), an analog of human IL-6, is usually lytic; production of vIL-6 by involved plasmablasts is a central feature of KSHV-MCD. vIL-6 also plays a role in PEL and KS. We show that a number of plasmablasts from lymph nodes of patients with KSHV-MCD express vIL-6 but not ORF45, a KSHV lytic gene. We further show that vIL-6 is directly induced by the spliced (active) X-box binding protein-1 (XBP-1s), a transcription factor activated by endoplasmic reticulum (ER) stress and differentiation of B cells in lymph nodes. The promoter region of vIL-6 contains several potential XBP-response elements (XREs), and two of these elements in particular mediate the effect of XBP-1s. Mutation of these elements abrogates the response to XBP-1s but not to the KSHV replication and transcription activator (RTA). Also, XBP-1s binds to the vIL-6 promoter in the region of these XREs. Exposure of PEL cells to a chemical inducer of XBP-1s can induce vIL-6. Patient-derived PEL tumor cells that produce vIL-6 frequently coexpress XBP-1, and immunofluorescence staining of involved KSHV-MCD lymph nodes reveals that most plasmablasts expressing vIL-6 also coexpress XBP-1. These results provide evidence that XBP-1s is a direct activator of KSHV vIL-6 and that this is an important step in the pathogenesis of KSHV-MCD and PEL.