Association of a Network of Interferon-Stimulated Genes with a Locus Encoding a Negative Regulator of Non-conventional IKK Kinases and IFNB1

Functional genomic analysis of gene expression in mice allowed us to identify a quantitative trait locus (QTL) linked in trans to the expression of 190 gene transcripts and in cis to the expression of only two genes, one of which was Ypel5. Most of the trans-expression QTL genes were interferon-stimulated genes (ISGs), and their expression in mouse macrophage cell lines was stimulated in an IFNB1-dependent manner by Ypel5 silencing. In human HEK293T cells, YPEL5 silencing enhanced the induction of IFNB1 by pattern recognition receptors and phosphorylation of TBK1/IKBKE kinases, whereas co-immunoprecipitation experiments revealed that YPEL5 interacted physically with IKBKE. We thus found that the Ypel5 gene (contained in a locus linked to a network of ISGs in mice) is a negative regulator of IFNB1 production and innate immune responses that interacts functionally and physically with TBK1/IKBKE kinases. [Display omitted] •One QTL associates in trans with expression of 190 genes in mouse cardiac tissue•Expression levels of the Ypel5 gene associate in cis with that QTL•Ypel5 regulates interferon-responsive genes present in the hotspot of trans-regulated genes•YPEL5 interacts functionally and physically with TBK1/IKBKE kinases Jeidane et al. find that a locus containing the Ypel5 gene is linked to the expression of interferon-responsive genes in mice. Further examination reveals that the Ypel5 gene is a negative regulator of IFNB1 production and non-conventional IKK kinases.