A ubiquitin ligase mediates target-directed microRNA decay independently of tailing and trimming.

MicroRNAs (miRNAs) act in concert with Argonaute (AGO) proteins to repress target mRNAs. After AGO loading, miRNAs generally exhibit slow turnover. An important exception occurs when miRNAs encounter highly complementary targets, which can trigger a process termed target-directed microRNA degradation (TDMD). During TDMD, miRNAs undergo tailing and trimming, suggesting that this is an important step in the decay mechanism. Here, we identified a cullin-RING ubiquitin ligase (CRL), containing the substrate adapter ZSWIM8, that mediated TDMD. The ZSWIM8 CRL interacted with AGO proteins, promoted TDMD in a tailing and trimming-independent manner, and regulated miRNA expression in multiple cell types. These findings suggest a model in which the ZSWIM8 ubiquitin ligase mediates TDMD by directing proteasomal decay of miRNA-containing complexes engaged with highly complementary targets.