The workings of GW182, a protein crucial for microRNA repression

Witold Filipowicz, a world leader in the field of small RNA function, has determined the mechanism of action of GW182, a protein crucial for gene silencing mediated by microRNAs. His team at the Friedrich Miescher Institute for Biomedical Research (FMI) showed that the GW182 protein recruits the deadenylation complex CCR4-NOT through its tryptophan-containing motifs, to target mRNA. It thereby not only facilitates degradation of mRNAs but also represses their translation. The results are now published online in Nature Structural & Molecular Biology.

One of the unexpected discoveries of the last 10 years is the important role played by short non-coding RNAs called microRNAs (miRNAs) in gene regulation. miRNAs interact in a sequence-specific way with target mRNAs and either inhibit their translation or induce mRNA deadenylation and degradation. Several proteins help these processes, among which are proteins of the GW182 family. These were known to be important for miRNA-mediated gene silencing, yet until recently it was unclear how GW182 proteins contribute to this process.

A group of scientists led by Witold Filipowicz of the Friedrich Miescher Institute for Biomedical Research has shed light on the repression mechanisms triggered by GW182. They identified sequence motifs in GW182 proteins that are crucial for mRNA repression. These tryptophane-containing motifs are dispersed across the polypeptides and act in an additive manner to recruit a repressive multi-protein effector complex, called CCR4-NOT. Once brought into the vicinity of mRNA, the CCR4-NOT complex deadenylates mRNA and thereby triggers its degradation. However, mRNA control does not stop there. The Filipowicz group next showed that the CCR4-NOT complex also induces translational repression of mRNAs, independently of their polyadenylation status. Hence, CCR4-NOT is responsible for mediating two of the major functions ascribed to miRNAs: translational inhibition and mRNA deadenylation. Finally, the FMI scientists could show that this mechanism of action is conserved between the fruit fly Drosophila melanogaster and man.

This is the first study demonstrating that GW182 proteins directly recruit the CCR4-NOT complex to repressed mRNAs and that tryptophan motifs are responsible for this process. Commenting on the importance of the work, Filipowicz says: "Our results add one more step to the complexity of miRNA regulation. With indications that miRNAs control expression of more than half of the human genes, it is not surprising that their activity is mediated by several layers of protein effectors. miRNAs directly recruit Argonaute proteins, Argonuates recruit GW182 proteins, and GW182 proteins - as shown here - recruit CCR4-NOT complexes. It is likely that miRNA repression is tightly regulated at each of these interaction levels. Since miRNAs are implicated in many human pathologies, future work on protein effectors of miRNA function may lead to the development of new therapies for human disease."

About Witold Filipowicz
Witold Filipowicz is a group leader at the FMI and also a professor at the University of Basel. As a pioneer in RNA research, he has studied this molecule long before the recent excitement around RNA interference (RNAi), microRNAs (miRNAs), and RNA's newly defined role in gene regulation arose. His results, synergizing with others in the field, not only paved the way for a new view of the function of RNA in the cell, but laid the groundwork for harnessing RNA-driven processes for biomedical purposes. In the last couple of years, in particular, his characterization of human Dicer, the protein catalyzing the first step in RNAi, and his work on the function and metabolism of miRNAs, have demonstrated that small RNA molecules play a key role in gene regulation.
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Original publication
Chekulaeva M, Mathys H, Zipprich JT, Attig J, Colic M, Parker R, Filipowicz W. (2011) miRNA repression involves GW182-mediated recruitment. Nature Structural & Molecular Biology, Oct 7.
doi:10.1038/nsmb.2166 [Epub ahead of print].