MIR155HG Plays a Bivalent Role in Regulating Innate Antiviral Immunity by Encoding Long Noncoding RNA-155 and microRNA-155-5p

MIR155HG encodes a precursor RNA of microRNA-155 (miRNA-155). We previously identified this RNA also as a long noncoding RNA (lncRNA) that we call lncRNA-155. To define the functions of miRNA-155 and lncRNA-155, we generated miRNA-155 knockout (KO) mice lacking only 19 bp of the miRNA-155 core sequence without affecting the expression of lncRNA-155. Surprisingly, compared with the miRNA-155KO mice, previously generated lncRNA-155KO mice were more susceptible to both influenza virus (RNA virus) and pseudorabies virus (DNA virus) infection, as characterized by lower survival rate, higher body weight loss, and higher viral load. We found that miRNA-155-5p enhanced antiviral responses by positively regulating activation of signal transducer and activator of transcription 1 (STAT1), but the STAT1 activity differed greatly in the animals (lncRNA-155KO < miRNA-155KO < wild type). In line with this, expression levels of several critical interferon-stimulated genes (ISGs) were also significantly different (lncRNA-155KO < miRNA-155KO < wild type). We found that lncRNA-155 augmented interferon beta (IFN-β) production during the viral infection, but miRNA-155 had no significant effect on the virus-induced IFN-β expression. Furthermore, we observed that lncRNA-155 loss in mice resulted in dramatic inhibition of virus-induced activation of interferon regulatory factor 3 compared to both miRNA-155KO and wild-type (WT) animals. Moreover, lncRNA-155 still significantly suppressed the viral infection even though the miRNA-155 derived from lncRNA-155 was deleted or blocked. These results reveal that lncRNA-155 and miRNA-155 regulate antiviral responses through distinct mechanisms, indicating a bivalent role for MIR155HG in innate immunity.