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

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 through binding to the 3'untranslated region (3'UTR). Among these, three miRNAs are particularly enriched in circulating monocytes which exhibit low baseline . Intriguingly, the 3'UTR sequence is duplicated in human and chimpanzee genomes. In humans, four 3'UTR copies were previously found to be embedded in long intergenic non-coding (linc) RNA genes residing in chr22q11.21 and known as . 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 ) that is expressed only in testis. RNA-seq data analyses from testicular cell subsets revealed a positive correlation between and 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.