Human USP18 is regulated by miRNAsviathe 3’UTR, a sequence duplicated in lincRNA genes residing in chr22q11.21

Abstract

ABSTRACTUbiquitin-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 interferon-stimulated transcripts. How the baseline level of USP18 is finely tuned in different cell types remains ill defined. Here we explored post-transcriptional regulation of USP18 by microRNAs (miRNAs) and identified four miRNAs (miR-24-3p, miR-191-5p, miR-423-5pandmiR-532-3p) that efficiently targetUSP18through binding to the 3’UTR. Among these, three miRNAs are particularly enriched in circulating monocytes which exhibit low baselineUSP18. Intriguingly, theUSP183’UTR sequence is duplicated in human and chimpanzee genomes. In human, we found several copies of the 3’UTR that are embedded in long intergenic non-coding (linc) RNA genes residing in chr22q11.21 and exhibiting a tissue-specific expression pattern. Interestingly, one of these lincRNAs (here namedlinc-UR-B1) is uniquely and highly expressed in testis. RNA-seq data analyses from testicular cell subsets revealed a positive correlation betweenlinc-UR-B1andUSP18expression 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.SIGNIFICANT STATEMENTUSP18 is a non-redundant negative feedback regulator of type I IFN signaling and a key determinant of cell responsiveness to IFN. How baseline USP18 is set in different human cell types is ill defined. We identified three microRNAs that restrain USP18 level notably in primary monocytes through binding the 3’UTR. We found several copies of the USP18 3’UTR embedded in long intergenic non-coding (linc) RNAs which reside in a complex region of human chromosome 22. These lincRNAs are expressed in a tissue-specific manner. We describe one lincRNA expressed only in testis, and most notably in germ cells. Correlative analyses suggest that microRNAs and lincRNAs may form a network controlling baseline USP18 and IFN responsiveness.