Zcchc11-dependent uridylation of microRNA directs cytokine expression

Abstract

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 expression1,2. 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 motifs5, and has been implicated in signalling pathways involved in cytokine expression6. 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.