Human Ubiquitin-Specific Peptidase 18 Is Regulated by microRNAs via the 3'Untranslated Region, A Sequence Duplicated in Long Intergenic Non-coding RNA Genes Residing in chr22q11.21

Abstract

Ubiquitin-specific peptidase 18 (USP18) acts as gatekeeper of type I interferon (IFN) responses by binding to the IFN receptor subunit IFNAR2 and preventing activation of the downstream JAK/STAT pathway. In any given cell type, the level of USP18 is a key determinant of the output of IFN-stimulated transcripts. How the baseline level of USP18 is finely tuned in different cell types remains ill defined. Here, we identified microRNAs (miRNAs) that efficiently target <i>USP18</i> through binding to the 3'untranslated region (3'UTR). Among these, three miRNAs are particularly enriched in circulating monocytes which exhibit low baseline <i>USP18</i>. Intriguingly, the <i>USP18</i> 3'UTR sequence is duplicated in human and chimpanzee genomes. In humans, four <i>USP18</i> 3'UTR copies were previously found to be embedded in long intergenic non-coding (linc) RNA genes residing in chr22q11.21 and known as <i>FAM247A-D</i>. Here, we further characterized their sequence and measured their expression profile in human tissues. Importantly, we describe an additional lincRNA bearing USP18 3'UTR (here <i>linc-UR-B1</i>) that is expressed only in testis. RNA-seq data analyses from testicular cell subsets revealed a positive correlation between <i>linc-UR-B1</i> and <i>USP18</i> expression in spermatocytes and spermatids. Overall, our findings uncover a set of miRNAs and lincRNAs, which may be part of a network evolved to fine-tune baseline USP18, particularly in cell types where IFN responsiveness needs to be tightly controlled.