Figure 7

DED proteins in MAVS signaling. Following viral infection of cells, viral RNA is detected by CARD-containing RIG-1-like receptors, for example, RIG-1 and MDA5. RIG-1 binds the dsRNA, exposing its normally hidden CARD domains. K63 ubiquitin chains are conjugated to the CARDs, facilitating the assembly of a complex composed of four polyubiquitin chains and four RIG-1 molecules (not shown).^{200, 201} This in turn induces the formation of prion-like aggregates of MAVS, which strongly activate IRF3.^{202, 203} These MAVS aggregates form a platform which can recruit TRAF2, TRAF3 and TRAF6.²⁰³ TRADD also binds MAVS followed by TANK and TBK2, activating antiviral IRF3.^{129, 203} However, TRADD can also recruit RIPK1, FADD and caspase-8, a complex dubbed the ‘TRADDosome’. Caspase-8 cleaves RIPK1 and the resulting RIPK1 fragment can inhibit IRF3, ceasing the antiviral response.²⁰⁴ RIPK1 is conjugated by K63 ubiquitin chains inducing two distinct signaling pathways from the TRADDosome: firstly, NF-κB signaling through NEMO, IKKα and IKKβ, and secondly NEMO can interact with NAP1, TBK1 and IKKɛ to activate IRF3 or IRF7.^{205, 206, 207, 208} In addition to caspase-8, the TRADDosome can also recruit FLIP (not shown) and may under certain conditions, trigger cell death