Repression of C. elegans microRNA targets at the initiation level of translation requires GW182 proteins

• Published in: The EMBO journal Vol. 28; no. 3; pp. 213 - 222
• Main Authors: Ding, Xavier C, Großhans, Helge
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 04-02-2009; Nature Publishing Group UK; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: 3' Untranslated Regions - metabolism; AIN-1; Animal models; Animals; Binding Sites; Caenorhabditis elegans - genetics; Caenorhabditis elegans - metabolism; Caenorhabditis elegans Proteins - metabolism; Carrier Proteins - metabolism; Cellular biology; EMBO31; EMBO36; Gene Expression Regulation; Genes, Helminth; let-7; lin-4; microRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Mode of action; Molecular biology; Physiology; Protein Biosynthesis; Proteins; Repressor Proteins - metabolism; Ribonucleic acid; RNA; RNA Stability; Stem cells; translational repression; Worms; microRNA; lin‐4; translational repression; AIN‐1; let‐7
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2008.275

MicroRNAs (miRNAs) repress target genes through a poorly defined antisense mechanism. Cell‐free and cell‐based assays have supported the idea that miRNAs repress their target mRNAs by blocking initiation of translation, whereas studies in animal models argued against this possibility. We examined endogenous targets of the
let‐7
miRNA, an important regulator of stem cell fates. We report that
let‐7
represses translation initiation in
Caenorhabditis elegans
, demonstrating this mode of action for the first time in an organism. Unexpectedly, although the
lin‐4
miRNA was previously reported to repress its targets at a step downstream of translation initiation, we also observe repression of translation initiation for this miRNA. This repressive mechanism, which frequently but not always coincides with transcript degradation, requires the GW182 proteins AIN‐1 and AIN‐2, and acts on several mRNAs targeted by different miRNAs. Our analysis of an expanded set of endogenous miRNA targets therefore indicates widespread repression of translation initiation under physiological conditions and establishes
C. elegans
as a genetic system for dissection of the underlying mechanisms.