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 USP18 through binding to the 3’untranslated region (3’UTR). Among these, three miRNAs are particularly enriched in circulating monocytes which exhibit low baseline USP18. Intriguingly, the USP18 3’UTR sequence is duplicated in human and chimpanzee genomes. In humans, four USP18 3’UTR copies were previously found to be embedded in long intergenic non-coding (linc) RNA genes residing in chr22q11.21 and known as FAM247A-D. 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 linc-UR-B1) that is expressed only in testis. RNA-seq data analyses from testicular cell subsets revealed a positive correlation between linc-UR-B1 and USP18 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.
Highlights
Ubiquitin-specific peptidase 18 (USP18) is an interferon (IFN)stimulated gene (ISG) exerting a specific and non-redundant role in the negative regulation of type I IFN responses (Honke et al, 2016; Basters et al, 2018)
Using the bioinformatic prediction programs miRWalk and RNAhybrid, we identified 27 miRNAs predicted to target with high score the 580 nt-long 3' untranslated regions (3'UTRs) of the human USP18 messenger RNAs (mRNAs) (Figure 1A)
We expressed in HeLa S3 cells, each miRNA as mimic and measured the level of USP18 mRNA by Quantitative PCR (qPCR)
Summary
Ubiquitin-specific peptidase 18 (USP18) is an interferon (IFN)stimulated gene (ISG) exerting a specific and non-redundant role in the negative regulation of type I IFN (here, IFN) responses (Honke et al, 2016; Basters et al, 2018). In mouse models of VSV and LCMV infection, it was shown that the ability of CD169+ spleen macrophages and dendritic cells to present viral antigens and elicit an innate and adaptive immunity relies on the expression of Usp (Honke et al, 2011, 2013). These findings point to USP18 as a key determinant of cell responsiveness to IFN, including in the context of constitutive low IFNβ levels. Little is known on how baseline USP18 levels are set in different cell lineages
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