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Zcchc11-dependent uridylation of microRNA directs cytokine expression

Authors
Journal
Nature Cell Biology
1465-7392
Publisher
Nature Publishing Group
Publication Date
Volume
11
Issue
9
Identifiers
DOI: 10.1038/ncb1931
Keywords
  • Article
Disciplines
  • Biology

Abstract

Zcchc11-dependent uridylation of microRNA directs cytokine expression Matthew R. Jones1,2, Lee J. Quinton1,2, Matthew T. Blahna1,2, Joel R. Neilson5, Suneng Fu3, Alexander R. Ivanov3, Dieter A. Wolf3,4, and Joseph P. Mizgerd1,2 1 The Pulmonary Center, Boston University School of Medicine, Boston, MA, 02115 2 Molecular and Integrative Physiological Sciences, Harvard, School of Public Health, Boston, MA 02115 3 Department of Genetics and Complex Diseases and NIEHS Center Proteomics Facility, Harvard, School of Public Health, Boston, MA 02115 5 Koch Institute for Integrative Cancer Research, Massachusetts Institute, of Technology, Cambridge, MA, 02139, USA 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 targeting their 3′ untranslated regions 3, 4. The Zcchc11 protein contains RNA-interacting motifs5, and it has been implicated in signaling 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 microRNAs. Zcchc11 is a ribonucleotidyltransferase with a preference for uridine and is essential to maintaining the poly(A) tail length and stability of transcripts for interleukin-6 (IL-6) and select other 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. While 78% of mir-26a sequences in control cells contained 1–3 uridines on their 3′ ends, less than 0.1% did so in Zcchc11 knock down cells. Thus, Zcchc11 fine tunes IL-6 production by uridylating mir-26a, which we propose to be an enzymatic modification of the terminal nucleotide sequence of mature miRNA as a means for regulating gene expression. Zcchc11 is a member of the DNA polymerase β-li

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