Jones, M. R. et al. Zcchc11-dependent uridylation of microRNA directs cytokine expression. Nature Cell Biol. 11, 1157-1163

The Pulmonary Center, Boston University School of Medicine, MA 102118,USA.
Nature Cell Biology (Impact Factor: 19.68). 09/2009; 11(9):1157-63. DOI: 10.1038/ncb1931
Source: PubMed


Mounting an effective host immune response without incurring inflammatory injury requires the precise regulation of cytokine expression. To achieve this, cytokine mRNAs are post-transcriptionally regulated by diverse RNA-binding proteins and microRNAs (miRNAs) targeting their 3' untranslated regions (UTRs). Zcchc11 (zinc-finger, CCHC domain-containing protein 11) contains RNA-interacting motifs, and has been implicated in signalling pathways involved in cytokine expression. The nature of the Zcchc11 protein and how it influences cytokine expression are unknown. Here we show that Zcchc11 directs cytokine expression by uridylating cytokine-targeting miRNAs. Zcchc11 is a ribonucleotidyltransferase with a preference for uridine and is essential for maintaining the poly(A) tail length and stability of transcripts for interleukin-6 (IL-6) and other specific cytokines. The miR-26 family of miRNAs targets IL-6, and the addition of terminal uridines to the miR-26 3' end abrogates IL-6 repression. Whereas 78% of miR-26a sequences in control cells contained 1-3 uridines on their 3' ends, less than 0.1% did so in Zcchc11-knockdown cells. Thus, Zcchc11 fine tunes IL-6 production by uridylating miR-26a, which we propose is an enzymatic modification of the terminal nucleotide sequence of mature miRNA as a means to regulate gene expression.

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    • "RNAs less stable (Scott and Norbury, 2013). In mammalian cells, ZCCHC11, a terminal uridyltransferase also known as TUT4, mediates terminal uracil additions of miR-26a, thereby abolishing its function, albeit its relative abundance appears unaffected (Jones et al., 2009). Enrichment of 3 0 uridylated "
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    • "The addition of non-templated nucleotides to the 3′ ends of RNA molecules is a widespread mechanism for their regulation. Beyond the familiar long poly(A) tails of messenger RNAs, short 3′ tailing of uridine [1-4] and adenosine [5-7] nucleotides to noncoding RNAs is gathering increasing appreciation. These simple oligonucleotide additions (one to ~20 identical bases) can alter the stability, binding partners or activity of the enzymatic reactions in which these RNAs participate. "
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