Figure 7

Retinoid action during paramyxovirus infection. (A) 1) Jak/STAT signaling is inhibited as a result of viral infection and ATRA treatment is unable to effectively promote unregulation of ISGs and type I IFN production. 2) Cells exposed to the products of the primary infection and primed with ATRA can more efficiently secrete type I IFN upon infection. (B) 3) Exposure to ATRA and type I IFN in the supernatant signals through the Jak/STAT pathway with the combination of nuclear localization of STAT1/2 heterodimer and activation of the RAR/RXR complex results in the transcription of multiple ISGs, importantly IRF1. For simplicity, only IFNα and its receptor IFNAR1/2 are shown to promote Jak/STAT signaling. 4) RIG-I expression is greatly up-regulated under these conditions, by IRF1 binding to the interferon response element (IRE) on its promoter. 5) Increased cytoplasmic quantities of RIG-I provide protection in the bystander cell upon virus infection. RIG-I detects viral RNA and associates with the adaptor protein MAVS, which initiates downstream activation of NFκB and IRF3/7. Nuclear translocation to their respective promoter elements induces transcription of antiviral genes, i.e., type I IFN and IRF1/7 production. It is not clear what role the second cytoplasmic RNA helicase (mda5) plays in this cascade although mda5 has been implicated in responses to several Paramyxoviridae. 6) These proteins feedback onto their respective pathways and promote RIG-I expression, further improving the antiviral state of the cell. 7) Increased production of type I IFN from the retinoid-primed bystander cell provides both an autocrine and paracrine signal to further protect the uninfected cells in culture.