miRNA-mediated deadenylation is orchestrated by GW182 through two conserved motifs that interact with CCR4–NOT

Abstract

The GW182 protein, which binds poly(A)-binding protein (PABP) and is part of the miRNA-induced silencing complex, effects translational repression and deadenylation of target mRNAs. New data indicate that GW182 independently interacts with the PAN2–PAN3 and CCR4–NOT deadenylase complexes and that interaction of GW182 with CCR4–NOT is PABP-independent and occurs through discrete binding sites with distinct roles in miRNA-mediated deadenylation. miRNAs recruit the miRNA-induced silencing complex (miRISC), which includes Argonaute and GW182 as core proteins. GW182 proteins effect translational repression and deadenylation of target mRNAs. However, the molecular mechanisms of GW182-mediated repression remain obscure. We show here that human GW182 independently interacts with the PAN2–PAN3 and CCR4–NOT deadenylase complexes. Interaction of GW182 with CCR4–NOT is mediated by two newly discovered phylogenetically conserved motifs. Although either motif is sufficient to bind CCR4–NOT, only one of them can promote processive deadenylation of target mRNAs. Thus, GW182 serves as both a platform that recruits deadenylases and as a deadenylase coactivator that facilitates the removal of the poly(A) tail by CCR4–NOT.