GW182 Proteins Directly Recruit Cytoplasmic Deadenylase Complexes to miRNA Targets

• Published in: Molecular cell Vol. 44; no. 1; pp. 120 - 133
• Main Authors: Braun, Joerg E., Huntzinger, Eric, Fauser, Maria, Izaurralde, Elisa
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07-10-2011
• Subjects: Animals; Carrier Proteins - metabolism; Cytoplasm - metabolism; Drosophila melanogaster; Drosophila Proteins - metabolism; Exoribonucleases - metabolism; Gene expression; Gene Silencing; Genetic Complementation Test; HeLa Cells; Humans; messenger RNA; microRNA; MicroRNAs - metabolism; miRNA; Poly A - metabolism; Polyadenylation; Post-transcription; Protein Interaction Mapping; Protein Structure, Tertiary; proteins; Receptors, CCR4 - metabolism; regulator genes; Retinoblastoma-Binding Protein 4 - metabolism; Ribonucleases - metabolism; Transcription Factors - metabolism; Translation; translation (genetics)
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2011.09.007

miRNAs are posttranscriptional regulators of gene expression that associate with Argonaute and GW182 proteins to repress translation and/or promote mRNA degradation. miRNA-mediated mRNA degradation is initiated by deadenylation, although it is not known whether deadenylases are recruited to the mRNA target directly or by default, as a consequence of a translational block. To answer this question, we performed a screen for potential interactions between the Argonaute and GW182 proteins and subunits of the two cytoplasmic deadenylase complexes. We found that human GW182 proteins recruit the PAN2-PAN3 and CCR4-CAF1-NOT deadenylase complexes through direct interactions with PAN3 and NOT1, respectively. These interactions are critical for silencing and are conserved in D. melanogaster. Our findings reveal that GW182 proteins provide a docking platform through which deadenylase complexes gain access to the poly(A) tail of miRNA targets to promote their deadenylation, and they further indicate that deadenylation is a direct effect of miRNA regulation.
[Display omitted]
► TNRC6 proteins interact with PAN3, a subunit of the PAN2-PAN3 deadenylase complex ► TNRC6 proteins interact with NOT1, a subunit of the CCR4-NOT deadenylase complex ► These interactions are direct and mediated by the TNRC6-silencing domains ► The CCR4-NOT complex provides the major contribution to miRNA target degradation