Figure 6

IRF3 signaling depends on a translocation of signaling upon proteasomal-degradation of MAVS. In non-activated cells, MAVS is associated to mitochondria through its C-terminal transmembrane domain. RLR activation induces MAVS oligomerization and aggregation [16] (to simplify the model, only two MAVS molecules are shown as forming an aggregate), then MAVS recruits TRAF3 and other E3 ubiquitin ligases which function to catalyze Lys 63-linked polyubiquitination of target proteins including TRAF3 itself. The Lys 63-linked polyubiquitin chains (in green) recruit NEMO which in turn binds to TBK1 and TBK1 is activated. Concomitantly, TRIM25 induces Lys 48-linked polyubiquitination (in red) of MAVS. The proteasomal degradation of MAVS results in the translocation of the MAVS-assembled complex into the cytosol where activated TBK1 phosphorylates IRF3 to promote type I IFN production.