Fig. 7

Model of ATPase-mediated discrimination of non-self RNA by MDA5. a Activation model of wt MDA5. In resting state, MDA5 is in an auto-repressed form with, by analogy with RIG-I, CARD(s) binding to hel that prevents direct access of any RNA to the hel domain. Upon encountering, a viral dsRNA binds to MDA5 hel (2). CTD binds to RNA and hel2i and induces CARD release and exposure of the self-oligomerization domain. This nucleates the binding of another MDA5 molecule on the same RNA (3) and so on so as to constitute a multivalent CARD signalling platform (4). The binding of dsRNA to the hel also allosterically favours ATP binding to the ATPase motor (2). This drives fast ATP hydrolysis (5) with allosteric release of the dsRNA from the hel domain of MDA5, disassembly of the oligomer into monomers that returns back to their auto-repressed state. b A serendipitous binding to cellular (self) RNA (1b) can induce ATP binding (2b) but the self RNA is evicted before any recruitment of another MDA5 can occur (that is, step 5 is prevalent over step 3). Consequently, there is no signal elicitation (4b). c Model of the constitutive activity of ATPase-deficient MDA5. MDA5-E444Q serendipitously binds to surrounding cellular (self) RNA via its hel domain (step 1b, not shown, see panel b) with binding of CTD to RNA and hel2i and exposure of both CARDs and oligomerization site. Because of the poor efficiency of its ATPase motor, step 5 cannot occur, the illegitimate self RNA cannot be expelled from the hel domain and multiple MDA5 in active state assemble into a long-lived multivalent platform (step 3) that keeps transducing the downstream signal (4c). Note that the multivalent platform may be made of MDA5 subunits bound to different short stretches of self RNA. CARD: caspase activation and recruitment domain; CTD: C-terminal domain; hel: helicase