期刊
NATURE CELL BIOLOGY
卷 11, 期 9, 页码 1157-U258出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncb1931
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- NCI NIH HHS [P01 CA42063, K99 CA131474, P01 CA042063-249002, P01 CA042063, K99 CA131474-02] Funding Source: Medline
- NCRR NIH HHS [S10 RR019028] Funding Source: Medline
- NHLBI NIH HHS [K99 HL092956-02, K99 HL092956, R01 HL079392, R01 HL079392-04, R01 HL068153, R01 HL068153-06] Funding Source: Medline
- NIEHS NIH HHS [P30 ES000002, P01 ES00002] Funding Source: Medline
- NIGMS NIH HHS [R01 GM059780] Funding Source: Medline
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.
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