Divergent target recognition by coexpressed 5′-isomiRs of miR-142-3p and selective viral mimicry

Abstract

Sequence heterogeneity at the ends of mature microRNAs (miRNAs) is well documented, but its effects on miRNA function are largely unexplored. Here we studied the impact of miRNA 5 ′ -heterogeneity, which affects the seed region critical for target recognition. Using the example of miR-142-3p, an emerging regulator of the hematopoietic lineage in vertebrates, we show that naturally coexpressed 5 ′ -variants (5 ′ -isomiRs) can recognize largely distinct sets of binding sites. Despite this, both miR-142-3p isomiRs regulate exclusive and shared targets involved in actin dynamics. Thus, 5′ -heterogeneity can substantially broaden and enhance regulation of one pathway. Other 5 ′ -isomiRs, in contrast, recognize largely overlapping sets of binding sites. This is exemplified by two herpesviral 5 ′ -isomiRs that selectively mimic one of the miR-142-3p 5 ′ -isomiRs. We hypothesize that other cellular and viral 5 ′ -isomiRs can similarly be grouped into those with divergent or convergent target repertoires, based on 5 ′ -sequence features. Taken together, our results provide a detailed characterization of target recognition by miR-142-3p and its 5 ′ -isomiR-specific viral mimic. We furthermore demonstrate that miRNA 5 ′ -end variation leads to differential targeting and can thus broaden the target range of miRNAs.

Japanese Macaque Rhadinovirus Encodes a Viral MicroRNA Mimic of the miR-17 Family

“…Similarly to what is observed for RRV and predicted for other rhadinoviruses, including RFHVMn and MneRV2 (4,(23)(24)(25), a KSHV miR-K10a/miR-142-3p seed homolog, miR-J15-3p, was identified for JMRV (Fig. 2E).…”

“…2E). KSHV miR-K10a is expressed as two isoforms that differ by 1 nucleotide at the 5= end to generate miR-K10a and miR-K10aϩ1 (25,42). Additionally, miR-K10 undergoes adenosine-to-inosine (A¡I) editing by adenosine deaminases acting on RNAs (ADARs) to generate miR-K10b (6,8,9,25,42).…”

“…Likely, rhadinovirus miRNA sequence conservation was overlooked in previous studies since the seed sequences of the miRNAs are not identical but rather are offset by 1 or 2 nucleotides. While it has been observed for some time that viral and cellular miRNAs with identical seed sequences can act as functional mimics (26,29), recent examples of viral miRNA seed sequence mimicry highlight that offset seed homology is also effective in binding 3= UTRs and repressing targets with cognate seed match sites (25,28). Thus, we predict that homology pairs such as JMRV miR-J11-5p and KSHV miR-K9-5p will have a common set of miRNA targets conserved in macaques and humans.…”

“…Despite their similar positions within each viral genome, RRV and KSHV miRNAs generally lack sequence homology, with a notable exception being RRV miR-rR1-15 and KSHV miR-K10a, which share a 5= seed sequence (10,23). Interestingly, this seed is also conserved in the predicted retroperitoneal fibromatosis-associated herpesvirus Macaca nemestrina (RFHVMn) miRNA miRc-RF-9-3p and exhibits homology to the seed region of cellular miR-142-3p, offset by one nucleotide (24,25). Recent biochemical studies demonstrate that KSHV miR-K10a can partly mimic miR-142-3p-mediated repression due to this offset seed sequence homology (25).…”

“…Interestingly, this seed is also conserved in the predicted retroperitoneal fibromatosis-associated herpesvirus Macaca nemestrina (RFHVMn) miRNA miRc-RF-9-3p and exhibits homology to the seed region of cellular miR-142-3p, offset by one nucleotide (24,25). Recent biochemical studies demonstrate that KSHV miR-K10a can partly mimic miR-142-3p-mediated repression due to this offset seed sequence homology (25). KSHV also encodes functional mimics of the cellular miRNAs miR-23a/b/c (KSHV miR-K3-5p) and miR-155 (KSHV miR-K11) that enable the virus to tap into conserved host miRNA-regulatory networks (26)(27)(28)(29).…”