Myd88 functions as a negative regulator of IRF11-mediated IFN production in teleosts

Abstract

MyD88 is an intracellular adaptor protein that mediates signals from many TLRs and IL-1/IL-18 receptors to downstream kinases, by recruiting transcription factors, such as IFN regulatory factor (IRF) family members, to evoke the activation of a series of target genes. Recent studies imply a role of MyD88 in the regulation of type IFN signaling through MyD88-IRF interaction in teleosts. In this study, we explore the mechanistic role of MyD88 on IFN production mediated by IRF11, a fish-specific positive regulator in this pathway. Overexpression of MyD88 suppressed IRF11-induced activation of the IFN promoter. Conversely, MyD88 knockdown in zebrafish liver cells further increased IRF11-induced expression of IFN and IFN-stimulated genes (ISGs). Co-immunoprecipitation experiments identified the Toll/IL-1 receptor (TIR) domain of MyD88 and the region between amino acids 114 and 155 of IRF11 as critical for their interaction. Confocal microscopy and subcellular fractionation revealed that MyD88 co-localizes with IRF11 in the nucleus upon co-expression. These results suggest MyD88 negatively regulates IRF11-mediated IFN production through protein-protein interaction and nuclear co-localization. Thus our present study places MyD88 as negative regulator participating in IRF11-mediated IFN production and provides a novel mechanism for regulating the fish antiviral response.