MicroRNAs (miRNAs) bind to and guide Argonaute (Ago) proteins to specific mRNAs through miRNA–mRNA base-pairing, resulting in mRNA cleavage and/or translation repression. Association with Ago usually confers a long half-life to the miRNA; however, base-pairing with some mRNAs (or long non-coding RNAs), which are referred to as trigger RNAs, initiates the decay of the miRNA itself. This partially understood process is called target-directed miRNA degradation (TDMD). The process requires the ubiquitin ligase ZSWIM8 complex, which ubiquitylates Ago, leading to its proteasomal degradation and consequently to the decay of the miRNA. Only a handful of trigger RNAs have been described (mostly in fruit flies), to which LaVigne, Han et al. add two in mice, showing they are required for embryonic growth.
The authors used an enhanced version of AGO-CLASH — a technique based on Ago cross-linking to hybrids of miRNA–trigger RNA — in mouse tissues to elucidate trigger RNAs that mediate TDMD during development. Next, using mouse fibroblasts, they showed that removal of the miR-322-5p binding site (putative ‘trigger site’) in the 3′ untranslated region (3′ UTR) of Plagl1 mRNA, and of the miR-503-5p putative trigger site in the 3′ UTR of Lrrc58 mRNA, reduced the decay of these miRNAs to a similar degree as ZSWIM8 loss. In the case of miR-503-5p, full abrogation of TDMD also required removal of a trigger site in the long non-coding RNA Malat1 (which is probably the first report of two TDMD triggers acting on the same miRNA). Thus, Plagl1, Lrrc58 and Malat1 act as TDMD triggers in mouse fibroblasts.
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