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 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.

Birth of a Regulatory Long Non-coding RNA/Gene, linc-UR-UB

“…At least one other known transcript, PTENJ2 shows some analogous properties. The Rubino et al (2021) study also adds to the multifaceted properties of 3'UTRs, properties that other investigators have previously described. For example, Mercer et al (2011) and Kocabas et al (2015) showed that many 3'UTR sequences are independently expressed in the absence of protein coding sequences and that their expression is regulated during development.…”

“…Although the evolutionary history of the formation of linc-UR-B1 is incomplete, the work of Rubino et al (2021) significantly advances our knowledge of gene birth by showing how linc-UR-B1 was created in humans. And there is beauty in the simplicity of this process-insertion of a small functional unit close to the end of an existing gene, utilizing the existing transcriptional apparatus and setting in place specific regulatory mechanisms for expression of this new gene in specific cells.…”

“…Thus, linc-UR-B1 is formed by read through transcription of the LOC102725072 gene to include the BCRP2 segment and the USP18 exon 11 3' UTR/3' end of the FAM247 sequence, which may be the functional key player. Linc-UR-B1 encodes two transcript isoforms termed TCONS_00029753 and TCONS_00029754 (Rubino et al, 2021). LOC102725072 by itself encodes RNA transcripts NR_135922 and NR_170942.1.…”

“…The recent paper by Sandra Pellegrini and co-workers in Frontiers in Genetics (Rubino et al, 2021) is multifaceted. The authors describe non-coding RNA components involved in the regulation of interferon and the JAK/STAT signaling pathway by the ubiquitin specific protease USP18, and they show binding of certain miRNAs to the USP18 mRNA 3' UTR, which is proposed to regulate USP18 expression.…”

Chemical and Biological Molecules Involved in Differentiation, Maturation, and Survival of Dopaminergic Neurons in Health and Parkinson’s Disease: Physiological Aspects and Clinical Implications

“…Using the miRNA as a guide, the RISC complex mediates the binding of the miRNA to the target mRNA, which results in gene silencing; a fully complementary pairing between the miRNA and the mRNA target results, indeed, in the cleavage of mRNA target. On the other side, the presence of some mismatches inhibits the translation by repressing the initial ribosome binding to the mRNA or the ribosome drop off [57][58][59].…”