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

Summary 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.