MDA5 (Melanoma Differentiation-Associated Gene 5)

MDA5 is a cytosolic double-stranded RNA sensor of the RIG-I-like receptor family. Upon binding dsRNA, MDA5 molecules cooperatively stack along the duplex to assemble a filamentous structure, which nucleates downstream signaling through the adaptor protein MAVS, activating IRF3 and driving type I interferon production. Because MDA5 cannot distinguish viral dsRNA from structurally similar endogenous dsRNA, cells rely on RNA-editing enzymes such as ADAR1 to destabilize self dsRNA and keep MDA5 from being inappropriately activated; loss of this restraint underlies autoinflammatory interferonopathies and can be exploited or suppressed in cancer to modulate antitumor immunity.