Figure 2.

Key Figure: RIG-I- and MDA5-Dependent Immunomodulatory Pathways

The RIG-I and MDA5 sensors are respectively activated by 5′ppp low molecular weight (LMW) and high molecular weight (HMW) viral RNA or viral intermediates containing double-stranded (ds) RNA structures. Ligand binding results in CARD-mediated interactions with the mitochondrial antiviral-signaling (MAVS) adaptor. MAVS activation results in the coordinated activation of the NF-κB and IRF3 transcription factors. NF-κB activation through the IKK α/β/γ kinase complex is in part mediated by a CARD9–BCL10-dependent pathway. IRF3 activation is dependent on the IKK-related TBK1/IKKε kinases. These in turn regulate the transcription of type I (orange spheres) and type III interferons (IFNs) (blue spheres), as well as of proinflammatory cytokines (purple spheres) including pro-IL-1β (double inverted pink triangle). RIG-I, but not MDA5, also mediates the activation of the inflammasome and subsequent caspase-1 activity (purple cylinder) that leads to the production of mature IL-1β (pink triangle). MDA5 is also involved in the regulation of the non-canonical NF-κB pathway and in the sustained activity of IRF3 by interfering with its proteasome-mediated degradation. Mechanisms currently uncharacterized are depicted by question marks. Abbreviations: P, phosphorylation; U, ubiquitination.