Induction of type I interferon by RNA viruses: cellular receptors and their substrates

Baum, Alina; García-Sastre, Adolfo

LGP2 activity was confirmed to be specific to RLR signaling as its expression had no effect on TLR3 mediated IFN induction. (Rothenfusser et al. 2005; Yoneyama et al. 2005) . The role of LGP2 as a negative regulator of RIG-I signaling was confirmed in Lgp2 -/-mice infected with VSV (Venkataraman et al. 2007 ). The exact mechanism by which LGP2 interferes with RIG-I signaling has not been resolved. One possibility is that LGP2 simply sequesters dsRNA from RIG-I. This potential mechanism is supported by LGP2's high binding affinity for poly(I:C) and synthetic dsRNA in vitro, and the high expression level of this protein following virus infection . Inhibition of RIG-I dimer formation has also been proposed as the possible mode of LGP2 inhibitory activity. This mechanism is supported by observed complex formation between LGP2 and RIG-I in infected cells and the structural similarity of LGP2 to RIG-I DCARD (Rothenfusser et al. 2005; Saito et al. 2007a ). Finally, observed association of LGP2 with MAVS in virus infected cells leads to a possible third mechanism for its activity. Komuro et al. demonstrated that LGP2 was able to compete with IKKe for MAVS binding, therefore inhibiting a downstream step in RIG-I mediated activation pathway (Komuro and Horvath 2006) . The RD of LGP2 when expressed alone is sufficient to inhibit RIG-I mediated signaling, but it is not as efficient as full length LGP2 (Murali et al. 2008) . Similarly to RIG-I RD, LGP2 RD is able to bind RNA and form dimers in vitro. The structure of LGP2 RD is very similar to that of the RIG-I RD (Pippig et al. 2009) . Surprisingly, binding assays with purified protein have revealed that LGP2 possesses no specificity to 5 0 ppp-RNA, and instead has very high affinity for any dsRNA, with the presence of phosphate groups appearing irrelevant. (Murali et al. 2008; Pippig et al. 2009 ). The RD of LGP2 has been shown to bind to the blunt-end of dsRNA and not to the phosphate backbone of the molecule (Li et al. 2009b ). Since RIG-I interacts with both 5 0 ppp-RNA and dsRNA, this finding still allows LGP2 to inhibit RIG-I signaling by dsRNA sequesteration or inhibition of RIG-I duplex formation. A recent study showed that LGP2 defective in RNA binding inhibited RIG-I to the same degree as wild-type LGP2; supporting the hypothesis that dsRNA sequesteration is not the primary mode of LGP2 mediated inhibition (Li et al. 2009b) .