The ZSWIM8 ubiquitin ligase mediates target-directed microRNA degradation

Turning the tables on microRNA decay MicroRNAs help to regulate many genes in animal cells. Each microRNA associates with an Argonaute (AGO) protein, forming a complex in which the microRNA pairs with a messenger RNA (mRNA) target and AGO recruits factors that accelerate mRNA decay. However, for some unusual targets, the reverse occurs: Pairing to the target recruits factors that accelerate microRNA decay rather than degradation of the mRNA. Working independently, Shi et al. and Han et al. elucidate the mechanism of this phenomenon. They found that pairing to the unusual targets recruits a ubiquitin ligase that causes degradation of AGO, thereby exposing the microRNA to cellular nucleases. Mutating the ubiquitin ligase in diverse animals and cell types deregulates numerous microRNAs, implying that this phenomenon is widely deployed to sculpt microRNA levels. Science , this issue p. eabc9359 , p. eabc9546