Alternative Splicing Transcripts of Zebrafish LGP2 Gene Differentially Contribute to IFN Antiviral Response

In mammals, RIG-I like receptors (RLRs) RIG-I and melanoma differentiation-associated gene 5 (MDA5) sense cytosolic viral RNA, leading to IFN antiviral response; however, LGP2 exhibits controversial functions. The same happens to fish LGP2. In this study we report that three zebrafish LGP2 splicing transcripts, a full-length LGP2, and two truncating variants, LGP2v1 and LGP2v2, play distinct roles during IFN antiviral response. Overexpression of the full-length LGP2 not only potentiates IFN response through the RLR pathway, in the absence or presence of poly(I:C) at limited concentrations, but also inhibits IFN response by relative high concentrations of poly(I:C) through functional attenuation of signaling factors involved in the RLR pathway; however, LGP2v1 and LGP2v2 only retain the inhibitory role. Consistently, LGP2 but not LGP2v1 and LGP2v2 confers protection on fish cells against spring viremia of carp virus (SVCV) infection and at limited expression levels, LGP2 exerts more significant protection than either RIG-I or MDA5. Further data suggest that in the early phase of SVCV infection, LGP2 functions as a positive regulator but along with SVCV replicating in cells up to a certain titer, which leads to a far more robust expression of IFN, LGP2 switches to a negative role. These in vitro results suggest an ingenious mechanism where the three zebrafish LGP2 splicing transcripts work cooperatively to shape IFN antiviral responses.