Inducible Major Vault Protein Plays A Pivotal Role In DsRNA-or Virus-Induced Proinflammatory Response

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. Here, we found in vitro that expression of MVP, interleukin (IL)6, and IL8 was inducible upon dsRNA stimulation or viral infection. Moreover, MVP was essential for the induction of IL6 and IL8, as impaired expression of IL6 and IL8 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 activator protein-1 (c-Fos) and CCAAT/enhancer binding protein (C/EBP?)-LAP to activate the IL6 and IL8 promoters. Introduction of mutations into the AP-1 and C/EBP? 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/EBP?. The interactions promoted nuclear translocation and recruitment of these transcription factors to IL6 and IL8 promoter regions.In 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. Together, our findings help to delineate a novel role of MVP in host proinflammatory response.