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Zcchc11-dependent uridylation of microRNA directs cytokine expression. Nat Cell Biol

The Pulmonary Center, Boston University School of Medicine, MA 102118,USA.
Nature Cell Biology (Impact Factor: 20.06). 09/2009; 11(9):1157-63. DOI: 10.1038/ncb1931
Source: PubMed

ABSTRACT 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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    • "In mammals, these distinct regulatory mechanisms have been partitioned into different orthologs, with the predominantly nucleolar Lin28B preferentially targeting pri- let-7 while the cytoplasmic Lin28/Lin28A acts via regulation of pre-let-7 [56]. The dual activities of Lin28/Lin28A on pre-let-7 are mediated at least in part through the ability of Lin28 to induce oligouridylation of pre-let-7 via the recruitment of ZCCHC11, the mammalian ncPAP that also uridylates mature miR-26a [57] and replication-dependent histone mRNAs (see Sections 3.1 and 2.2) [53]. Though ZCCHC11 interacts only transiently with pre-let-7 alone, the interaction is stabilised approximately 100-fold by the presence of Lin28 [58], resulting in the stable association of ZCCHC11 with pre-let-7 only as part of a ternary Lin28/ZCCHC11/pre-let-7 complex [59] [60]. "
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