Zcchc11-dependent uridylation of microRNA directs cytokine expression

The RNA-binding protein Zcchc11 regulates cytokine expression in response to inflammation, although it was unclear how. Zcchc11 is shown to be an uridyltransferase that acts on mature cytokine-targeting miR-26b to influence interleukin-6 expression. Mounting an effective host immune response without incurring inflammatory injury requires the precise regulation of cytokine expression 1 , 2 . To achieve this, cytokine mRNAs are post-transcriptionally regulated by diverse RNA-binding proteins and microRNAs (miRNAs) targeting their 3′ untranslated regions (UTRs) 3 , 4 . Zcchc11 (zinc-finger, CCHC domain-containing protein 11) contains RNA-interacting motifs 5 , and has been implicated in signalling pathways involved in cytokine expression 6 . 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.