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.

Multicohort analysis reveals baseline transcriptional predictors of influenza vaccination responses

“…Last, MVP is the major subunit of the vault complex, a multiprotein structure involved in nucleocytoplasmic transport. It is induced by double-stranded RNA and virus infection and is essential for the induction of interleukin-6 (IL-6) and IL-8, suggesting an important role in host proinflammatory response (59). High expression of MVP has been shown to suppress viral replication by inducing a type 1 interferon response through nuclear factor κB, establishing a further link with the inflammatory component identified in the module analysis (60).…”

Major vault protein plays important roles in viral infection

“…MVP is involved in the diversely cellular processes, including multiresistant cancers, signal transmission pathways, and immune response associated with viral infection and treatment . Viruses with divergent virulence and spreadways can cause diverse human diseases with different types and degrees of damage, as a response of viral infection, studies have confirmed that MVP is enhanced in diverse viral infection, including HBV, HCV, HIV, IAV and VSV, and so on.…”

“…The interferon regulatory factor 7 (IRF7) plays the master transcriptional role in viral infection‐induced IFN production and immune responses, activates IFN‐β production mediated by MyD88 (myeloid differentiation primary response 88)‐independent RIG‐1/MDA5 pathway, also activates IFN‐α production mediated by the MyD88‐dependent TLRs pathway . The IFN‐1 inhibits viral replication (including HCV, influenza A virus [IAV], and HIV) by the production of IFN‐stimulated effective proteins …”

“…MVP, as a regulator in the proinflammatory response and an effector in IFN signaling pathway, increases to against viral replication during viral infection . MVP has been proven to be a nuclear–cytoplasmic transport protein and interacts with c‐Fos of the AP‐1 complex components and C/EBPβ‐LAPs . The interaction promotes the AP‐1 complex and C/EBPβ‐LAPs translocation from the cytoplasm to nucleus and follows to activate the IL‐6 and IL‐8 expression by the AP‐1 complex and C/EBPβ‐LAPs binding to the IL6 and IL8 promoters, and MVP plays a synergistic role in the expression of IL‐6 and IL‐8 .…”

“…[44][45][46] The IFN-1 inhibits viral replication (including HCV, influenza A virus [IAV], and HIV) by the production of IFN-stimulated effective proteins. 11,47,48 After host cells or tissues are infected by HCV, PRRs of host cells recognize stimulation signals of products of HCV processing, the interaction between PRRs and stimulation signals activates IkBa kinase to phosphorylate IkBα, 49 which is associated with NF-kB protein complex in the cytoplasm, phosphorylated IkBα is released from NF-kB complex and degraded by ubiquitin-proteasome pathway, 50 free NF-kB complex translocates to the nucleus, and subsequently activates MVP transcription under coactivators including HCV protein NS5A. 11 HCV infection also induces MVP expression through the SP1 signal pathways, and the infection of vesicular stomatitis virus (VSV), IAV, and enterovirus 71 (EV71) has the same effect with HCV infection.…”