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

Baum, Alina; García-Sastre, Adolfo

Unlike its negative regulation of RIG-I induced signaling, LGP2 appears to have an enhancing effect on MDA5 specific IFN induction. Similarly to its complex formation with RIG-I, LGP2 has been found to interact with MDA5 in infected cells (Saito et al. 2007a ). The initial observation that LGP2 might act as a positive regulator of MDA5 came from an observation that LGP2 knockout mice infected with EMCV exhibited reduced levels of IFN in sera and increased mortality. In agreement with the in vivo results, LGP2 knockout MEFs were also severely limited in IFN production after poly(I:C) transfection (Venkataraman et al. 2007 ). Since the same animals were more resistant to infections with RIG-I specific viruses, these results suggested a differential role of LGP2 in regulation of RIG-I and MDA5 signaling. Supporting this hypothesis is a recent study showing that poly(I:C) activation of MDA5 peaked in the presence of an equal ratio of LGP2, and that LGP2 constructs deficient in RNA binding or individual domains alone were not capable of augmenting MDA5 directed signaling (Pippig et al. 2009 ). Also supporting the possible unique link between MDA5 and LGP2 is a study showing that paramyxovirus V proteins interact with both MDA5 and LGP2, but not RIG-I. This helicase domain mediated interaction leads to reduction of ATPase activity of both receptors (Parisien et al. 2009 ). The possible role of LGP2 as a negative regulator of RIG-I and a positive regulator of MDA5 is very puzzling since the two receptors are thought to act in parallel to induce IFN following virus infection. Possible abundance and expression kinetic differences of these three proteins in various cell types may account for this intriguing observation.