Inducible Major Vault Protein Plays a Pivotal Role in Double-Stranded RNA– or Virus-Induced Proinflammatory Response
Inducible Major Vault Protein Plays a Pivotal Role in Double-Stranded RNA– or Virus-Induced Proinflammatory Response
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DOI：
10.4049/jimmunol.1501481
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发表时间：
2016-03
期刊：
影响因子：
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通讯作者：
N. Peng;Shi Liu;Zhang-chuan Xia;Sheng Ren;Jian Feng;Mingzhen Jing;Xin Gao;E. Wiemer;Ying Zhu
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文献类型：
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作者：
N. Peng;Shi Liu;Zhang-chuan Xia;Sheng Ren;Jian Feng;Mingzhen Jing;Xin Gao;E. Wiemer;Ying Zhu
病原体入侵通过不同的转录因子信号通路触发强大的抗病毒细胞因子的产生。我们之前已经证明，主要穹窿蛋白（MVP）在病毒感染期间诱导 I 型干扰素的产生；然而，人们对 MVP 在促炎症反应中的作用知之甚少。在这项研究中，我们在体外发现 MVP、IL-6 和 IL-8 的表达在 dsRNA 刺激或病毒感染时是可诱导的。此外，MVP对于IL-6和IL-8的诱导至关重要，因为在缺乏MVP的人PBMC、人肺上皮细胞（A549）和THP-1单核细胞以及来自MVP敲除（MVP−/−）小鼠的小鼠脾细胞、腹膜巨噬细胞和PBMC中观察到IL-6和IL-8的表达受损。通过对潜在机制的研究，我们证明 MVP 与 AP-1 (c-Fos) 和 CCAAT/增强子结合蛋白 (C/EBP)β-肝脏富集的转录激活蛋白协同作用，激活 IL6 和 IL8 启动子。 IL6 和 IL8 启动子上的 AP-1 和 C/EBPβ 结合位点引入突变导致与 MVP 的协同激活作用丧失。此外，我们发现 MVP 与 c-Fos 和 C/EBPβ 相互作用。这种相互作用促进了这些转录因子的核易位和招募至 IL6 和 IL8 启动子区域。在 MVP−/− 小鼠模型中，早期抗病毒细胞因子表达显着降低，导致感染致命甲型流感病毒后肺部病毒滴度更高、死亡率更高、肺部损伤更严重。总而言之，我们的研究结果有助于描述 MVP 在宿主促炎症反应中的新作用。
Pathogen invasion triggers robust antiviral cytokine production via different transcription factor signaling pathways. We have previously demonstrated that major vault protein (MVP) induces type I IFN production during viral infection; however, little is known about the role of MVP in proinflammatory responses. In this study, we found in vitro that expression of MVP, IL-6, and IL-8 was inducible upon dsRNA stimulation or viral infection. Moreover, MVP was essential for the induction of IL-6 and IL-8, as impaired expression of IL-6 and IL-8 in MVP-deficient human PBMCs, human lung epithelial cells (A549), and THP-1 monocytes, as well as in murine splenocytes, peritoneal macrophages, and PBMCs from MVP-knockout (MVP−/−) mice, was observed. Upon investigation of the underlying mechanisms, we demonstrated that MVP acted in synergy with AP-1 (c-Fos) and CCAAT/enhancer binding protein (C/EBP)β–liver-enriched transcriptional activating protein to activate the IL6 and IL8 promoters. Introduction of mutations into the AP-1 and C/EBPβ binding sites on the IL6 and IL8 promoters resulted in the loss of synergistic activation with MVP. Furthermore, we found that MVP interacted with both c-Fos and C/EBPβ. The interactions promoted nuclear translocation and recruitment of these transcription factors to IL6 and IL8 promoter regions. In the MVP−/− mouse model, significantly decreased expression of early antiviral cytokines resulted in higher viral titer in the lung, higher mortality, and heavier lung damage after infection with lethal influenza A virus. Taken together, our findings help to delineate a novel role of MVP in host proinflammatory response.