The E3 ubiquitin ligase mechanism specifying targeted microRNA degradation

Within each complex, the miRNA pairs to target RNAs, and AGO provides effector function while also protecting the miRNA from cellular nucleases. Although much is known about miRNA-directed gene regulation, less is known about how miRNAs themselves are regulated.

One pathway that regulates miRNAs involves unusual targets called ‘trigger’ RNAs, which reverse the canonical regulatory logic and instead down-regulate miRNAs. This target-directed miRNA degradation (TDMD) is thought to require a cullin–RING E3 ligase because it depends on the cullin protein CUL3 and other ubiquitylation components, including the BC-box protein ZSWIM8. ZSWIM8 is required for murine perinatal viability and for destabilization of most short-lived miRNAs, which suggests biological importance of TDMD.