ATP Hydrolysis Enhances RNA Recognition and Antiviral Signal Transduction by the Innate Immune Sensor

Laboratory of genetics and physiology 2 (LGP2) is a member of the RIG-I-like receptor family of cytoplasmic pattern recog- nition receptors that detect molecular signatures of virus infec- tion and initiate antiviral signal transduction cascades. The ATP hydrolysis activity of LGP2 is essential for antiviral signaling, but it has been unclear how the enzymatic properties of LGP2 regulate its biological response. Quantitative analysis of the dsRNA binding and enzymatic activities of LGP2 revealed high dsRNA-independent ATP hydrolysis activity. Biochemical assays and single-molecule analysis of LGP2 and mutant vari- ants that dissociate basal from dsRNA-stimulated ATP hydrol- ysis demonstrate that LGP2 utilizes basal ATP hydrolysis to enhance and diversify its RNA recognition capacity, enabling the protein to associate with intrinsically poor substrates. This property is required for LGP2 to synergize with another RIG-I- like receptor, MDA5, to potentiate IFN transcription in vivo during infection with encephalomyocarditis virus or transfec- tion with poly(I:C). These results demonstrate previously unrec- ognized properties of LGP2 ATP hydrolysis and RNA interac- tion and provide a mechanistic basis for a positive regulatory role for LGP2 in antiviral signaling. The mammalian type I interferon (IFN) response is a power- ful antiviral system that directly interferes with virus replication and contributes to both innate and adaptive immune responses. Intracellular accumulation of virus replication intermediates such as double-stranded RNA (dsRNA) or RNAs with triphos- phorylated 5-ends are detected by cytosolic pattern recogni-