title: Inducible Major Vault Protein Plays a Pivotal Role in Double-Stranded RNA- or Virus-Induced Proinflammatory Response.
abstract: 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.
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and.
authors: Nanfang
authors: N
authors: Peng
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and.
authors: Shi
authors: S
authors: Liu
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and.
authors: Zhangchuan
authors: Z
authors: Xia
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and.
authors: Sheng
authors: S
authors: Ren
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and.
authors: Jian
authors: J
authors: Feng
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and.
authors: Mingzhen
authors: M
authors: Jing
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and.
authors: Xin
authors: X
authors: Gao
authors: Department of Medical Oncology, Erasmus University Medical Center Cancer Institute, Rotterdam 3000 CA, the Netherlands.
authors: Erik A C
authors: EA
authors: Wiemer
authors: State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, Hubei 430072, China; and yingzhu@whu.edu.cn.
authors: Ying
authors: Y
authors: Zhu
mesh_terms: D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology*; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D007109:Immunity / Q000235:genetics; D007249:Inflammation / Q000276:immunology*; D009980:Influenza A virus / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D012330:RNA, Double-Stranded / Q000276:immunology; D034741:RNA, Small Interfering / Q000235:genetics; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics / Q000378:metabolism*; D000099187:Major Vault Protein
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D016207:Cytokines; D012330:RNA, Double-Stranded; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein