Ribosomal protein L24 mediates mammalian microRNA processing in an evolutionarily conserved manner

Yonat Tzur, Serafima Dubnov, Nimrod Madrer, Adi Bar, Bettina Nadorp, Nibha Mishra, Paul Heppenstall, Estelle R. Bennett, David S. Greenberg, Katarzyna Winek*, Hermona Soreq*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

To investigate the mechanism(s) underlying the expression of primate-specific microRNAs (miRs), we sought DNA regulatory elements and proteins mediating expression of the primate-specific hsa-miR-608 (miR-608), which is located in the SEMA4G gene and facilitates the cholinergic blockade of inflammation by targeting acetylcholinesterase mRNA. ‘Humanized’ mice carrying pre-miR-608 flanked by 250 bases of endogenous sequences inserted into the murine Sema4g gene successfully expressed miR-608. Moreover, by flanking miR-608 by shortened fragments of its human genome region we identified an active independent promoter within the 150 nucleotides 5′ to pre-miR-608, which elevated mature miR-608 levels by 100-fold in transfected mouse- and human-originated cells. This highlighted a regulatory role of the 5′ flank as enabling miR-608 expression. Moreover, pull-down of the 150-base 5′ sequence revealed its interaction with ribosomal protein L24 (RPL24), implicating an additional mechanism controlling miR-608 levels. Furthermore, RPL24 knockdown altered the expression of multiple miRs, and RPL24 immunoprecipitation indicated that up- or down-regulation of the mature miRs depended on whether their precursors bind RPL24 directly. Finally, further tests showed that RPL24 interacts directly with DDX5, a component of the large microprocessor complex, to inhibit miR processing. Our findings reveal that RPL24, which has previously been shown to play a role in miR processing in Arabidopsis thaliana, has a similar evolutionarily conserved function in miR biogenesis in mammals. We thus characterize a novel extra-ribosomal role of RPL24 in primate miR regulation. Graphical abstract: [Figure not available: see fulltext.].

Original languageEnglish
Article number55
JournalCellular and Molecular Life Sciences
Volume81
Issue number1
DOIs
StatePublished - Dec 2024

Bibliographical note

Publisher Copyright:
© 2024, The Author(s).

Keywords

  • DDX5
  • Hsa-miR-608
  • miR processing
  • Pre-miRs
  • Pri-miRs
  • RPL24

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