Fraternity of old‐timers: How ubiquitin regulates miRNA functions

Abstract

miRNA‐mediated gene repression and ubiquitin‐dependent processes are among the oldest and most versatile mechanisms that control multiple molecular pathways, rather than just protein turnover. These systems were discovered decades ago and have become among the most studied. All systems within cells are interconnected, and these two are no exception: the plethora of studies have demonstrated that the activity of the miRNAs system depends on players of the ubiquitin‐centered universe of processes, and vice versa. This review focuses on recent progress that highlights that very similar mechanisms of regulation of miRNAs by ubiquitin‐related processes are likely to be found in distantly related species, including animals, plants, and viruses. Most of them occur through the ubiquitination of Argonaute proteins, but some of the other miRNA system factors are also regulated. This suggests that their regulatory relationships are either ancient evolutionary acquisitions or have arisen independently in different kingdoms.

Evidence of target-mediated miRNA degradation inDrosophilaovarian cell culture

“…One may suggest that the possible functions of the Dora-mediated ubiquitination and proteolysis of Ago1 is the elimination of such locked and nonfunctional Ago1 engaged with TDMD target from the cellular pool. This would make TDMD complementary to the mechanism of the control of quantity and quality of the unloaded Ago (Ryazansky and Akulenko 2023). If so, the knock-out of Dora should reduce the fraction of the functionally active Ago1 and derepress miRNA targets.…”

“…In S2 cell culture Dora is able to recognize only Ago1-bound miRNAs, but not Ago2-bound small RNAs mostly belonging to endo-siRNAs (Kingston et al 2022). The bioinformatic search revealed that SWIM8 orthologs are encoded in the genomes of animals, but not in Protozoa, plants, or fungi (Ryazansky and Akulenko 2023). So, the targeted degradation of miRNAs mediated by ZSWIM8 homologs seems to be widely distributed across Metazoa species.…”