Screening of Drosophila microRNA-degradation sequences reveals Argonaute1 mRNA’s role in regulating miR-999

Peike Sheng, Lu Li (), Tianqi Li, Yuzhi Wang, Nicholas M. Hiers, Jennifer S. Mejia, Jossie S. Sanchez, Lei Zhou () and Mingyi Xie ()
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Peike Sheng: University of Florida
Lu Li: University of Florida
Tianqi Li: University of Florida
Yuzhi Wang: University of Florida
Nicholas M. Hiers: University of Florida
Jennifer S. Mejia: University of Florida
Jossie S. Sanchez: University of Florida
Lei Zhou: University of Florida
Mingyi Xie: University of Florida

Nature Communications, 2023, vol. 14, issue 1, 1-14

Abstract: Abstract MicroRNAs (miRNA) load onto AGO proteins to target mRNAs for translational repression or degradation. However, miRNA degradation can be triggered when extensively base-paired with target RNAs, which induces confirmational change of AGO and recruitment of ZSWIM8 ubiquitin ligase to mark AGO for proteasomal degradation. This target RNA-directed miRNA degradation (TDMD) mechanism appears to be evolutionarily conserved, but recent studies have focused on mammalian systems. Here, we performed AGO1-CLASH in Drosophila S2 cells, with Dora (ortholog of vertebrate ZSWIM8) knockout mediated by CRISPR-Cas9 to identify five TDMD triggers (sequences that can induce miRNA degradation). Interestingly, one trigger in the 3′ UTR of AGO1 mRNA induces miR-999 degradation. CRISPR-Cas9 knockout of the AGO1 trigger in S2 cells and in Drosophila specifically elevates miR-999, with concurrent repression of the miR-999 targets. AGO1 trigger knockout flies respond poorly to hydrogen peroxide-induced stress, demonstrating the physiological importance of this TDMD event.

Date: 2023
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DOI: 10.1038/s41467-023-37819-9

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