LGP2 binds to PACT to regulate RIG-I– and MDA5-mediated antiviral responses

Abstract

The retinoic acid–inducible gene I (RIG-I)–like receptors (RLRs) RIG-I, MDA5, and LGP2 stimulate inflammatory and antiviral responses by sensing nonself RNA molecules produced during viral replication. Here, we investigated how LGP2 regulates the RIG-I– and MDA5-dependent induction of type I interferon (IFN) signaling and showed that LGP2 interacted with different components of the RNA-silencing machinery. We identified a direct protein-protein interaction between LGP2 and the IFN-inducible, double-stranded RNA binding protein PACT. The LGP2-PACT interaction was mediated by the regulatory C-terminal domain of LGP2 and was necessary for inhibiting RIG-I–dependent responses and for amplifying MDA5-dependent responses. We described a point mutation within LGP2 that disrupted the LGP2-PACT interaction and led to the loss of LGP2-mediated regulation of RIG-I and MDA5 signaling. These results suggest a model in which the LGP2-PACT interaction regulates the inflammatory responses mediated by RIG-I and MDA5 and enables the cellular RNA-silencing machinery to coordinate with the innate immune response.

Mutual Regulation of RNA Silencing and the IFN Response as an Antiviral Defense System in Mammalian Cells

“…In addition, TRBP and PACT reportedly interact with LGP2 to regulate IFN production during infection with Theiler's murine encephalomyelitis virus (TMEV) or encephalomyocarditis virus (EMCV), but not during SeV infection [28][29][30]; this finding contrasts with our result that TRBP-LGP2 interaction occurs during SeV infection [27]. This discrepancy during SeV infection of TRBP-LGP2 interactions may result from differences in viral titer.…”

“…This specificity may be the reason that RNA silencing and the IFN response have been considered two independent pathways, despite both being induced by dsRNAs in the cytoplasm. However, recent reports, including ours, have provided a novel perspective that RNA silencing and the IFN response are mutually regulated through protein-protein interactions triggered by RNA virus infection [26][27][28][29][30][31][32][33]. In this review, we provide brief overviews of RNA silencing and the IFN response, and outline the molecular mechanism of their crosstalk with consideration of its biological implications.…”

Dance with the Devil: Stress Granules and Signaling in Antiviral Responses

“…LGP2 has been shown to localize in SGs upon IAVΔNS1 infection [ 242 ]. Moreover, the positive activator of PKR (PACT, PRKRA) was identified as an LGP2 interactor essential for RLR regulation [ 327 ], and also shown to localize in SGs upon treatment with hippuristanol [ 257 ], a steroid compound that interferes with cap-dependent translation [ 270 ]. Interestingly, PACT was also found in a complex with RIG-I and MDA5, positively regulating their downstream signaling [ 328 , 329 ].…”

Harnessing the Complete Repertoire of Conventional Dendritic Cell Functions for Cancer Immunotherapy

“…Whereas RIG-I or MDA5 are in charge for sensing either short or long double stranded RNA (dsRNA) leading to subsequent production of type I IFNs and pro-inflammatory cytokines via IRFs and NF-κB, LGP2 is thought to regulate other RLRs [ 110 , 155 ]. Even though the role of LGP2 during RLR dependent anti-viral responses is differentially discussed in the literature, a recent study suggests that LGP2 boosts MDA5 dependent responses, while ameliorating RIG-I pathways partially by coordinating post transcriptional RNA silencing programs [ 156 , 157 ]. In addition to dsRNA, RNA polymerase III activity enables the RIG-I dependent sensing of viral dsDNA following translation to a poly(dA:dT) dsRNA [ 158 ].…”