Figure 1.

Virus-activated intracellular signaling pathways. The recognition of viral nucleic acids by cellular sensors, also known as PRRs, includes endosomal TLRs and RLRs triggering downstream signaling cascades to activate transcription factors such as IRF3 and NF-κB. These transcription factors mediate the induction of type-I IFN. Type-I IFN includes IFNα/β, which bind to IFN receptors (IFNARs) to activate the JAK/STAT signaling pathway. In this signaling pathway, the canonical signal transducers and activators of transcription (STAT)-1 and 2 dimerize with IRF9 and form a signaling complex. This binds to IFN-stimulated response elements (ISREs) to induce ISGs that elicit an antiviral state in the cell. Recently, two non-transcriptional functions of IRF3, namely RIPA and RIKA, have been uncovered. RIPA (RIG-I-like receptor-induced IRF3-mediated pathway of apoptosis) involves linear polyubiquitination of IRF3 upon viral infection, resulting in the activation of downstream caspases that apoptotically kill virus-infected cells. On the other hand, RIKA (repression of IRF3-mediated NF-κB activity) is involved in the downregulation of viral inflammation.