Enzyme

Proteasome

Cullin

Ubiquitin-Protein Ligases

Biology

Gene

Ubiquitin ligase

Gene silencing

RNA interference

microRNA

DNA ligase

Argonaute

Ubiquitin

Proteolysis

Cell biology

Genetics

Biochemistry

Science

MicroRNAs (miRNAs) associate with Argonaute (AGO) proteins to direct widespread posttranscriptional gene repression. Although association with AGO typically protects miRNAs from nucleases, extensive pairing to some unusual target RNAs can trigger miRNA degradation. We found that this target-directed miRNA degradation (TDMD) required the ZSWIM8 Cullin-RING E3 ubiquitin ligase. This and other findings support a mechanistic model of TDMD in which target-directed proteolysis of AGO by the ubiquitin-proteasome pathway exposes the miRNA for degradation. Moreover, loss-of-function studies indicated that the ZSWIM8 Cullin-RING ligase accelerates degradation of numerous miRNAs in cells of mammals, flies, and nematodes, thereby specifying the half-lives of most short-lived miRNAs. These results elucidate the mechanism of TDMD and expand its inferred role in shaping miRNA levels in bilaterian animals.

The ZSWIM8 ubiquitin ligase mediates target-directed microRNA degradation