Zcchc11-dependent uridylation of microRNA directs cytokine expression

Jones, Matthew R.; Quinton, Lee J.; Blahna, Matthew T.; Neilson, Joel R.; Fu, Suneng; Ivanov, Alexander R.; Wolf, Dieter A; Mizgerd, Joseph P.

doi:10.1038/ncb1931

Cited by 279 publications

(281 citation statements)

References 40 publications

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“…Besides TIA-1, other proteins have been KSRP has been demonstrated to regulate maturation of a group of miRNAs, including miR-26b and let-7a (37). We did not obtain evidence for the contribution of these miRNAs, which have been reported to control IL-6 expression (25,26), to restricted translation of IL-6 mRNA in our experimental setting. However, it is well possible that under different condi-tions, e.g.…”

Section: Discussioncontrasting

confidence: 59%

“…Activators like IL-1 and lipopolysaccharide induce IL-6 mRNA stabilization through p38 MAPK/MK2 signaling (14, 24). IL-6 expression is also controlled by miRNAs (25,26).Our recent data showed that, in addition to stabilizing mRNAs, IL-1 can activate translation of mRNAs, including that of . We now provide evidence that repressed basal translation of IL-6 and a group of other mRNAs depends on KSRP.…”

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confidence: 99%

“…Activators like IL-1 and lipopolysaccharide induce IL-6 mRNA stabilization through p38 MAPK/MK2 signaling (14, 24). IL-6 expression is also controlled by miRNAs (25,26).…”

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confidence: 99%

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Interleukin-1 Activates Synthesis of Interleukin-6 by Interfering with a KH-type Splicing Regulatory Protein (KSRP)-dependent Translational Silencing Mechanism

Dhamija

Kuehne

Winzen

et al. 2011

Journal of Biological Chemistry

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Inflammatory gene expression is controlled by post-transcriptional mechanisms. Many relevant transcripts contain AU-rich elements (AREs) 4 that can impose rapid degradation and restrict translation (1-3). Several proteins that interact with and mediate the effects of AREs have been identified. One of them, heterogeneous nuclear ribonucleoprotein K homology (KH)-type splicing regulatory protein (KSRP) is a member of the far upstream sequence element-binding proteins (4). It is a single-stranded nucleic acid-binding protein that contains four KH domains and has been reported to participate in transcription as well as splicing, editing, localization, and degradation of mRNAs and maturation of microRNA precursors (for a review, see Ref. 5). Most recently it has been found to contribute to regulation of RNA 3Ј-end processing (6).KSRP has been shown to facilitate mRNA degradation by directly binding to AREs and recruiting mRNA-degrading enzymes (7,8). Ksrp Ϫ/Ϫ cells and mice produce more type I interferons as a result of decreased mRNA decay and are refractory to viral infection (9). Different conditions of cellular activation or differentiation have been described to reduce KSRP binding and increase stability of specific mRNAs (e.g. Refs. 10 -13). The proinflammatory cytokine IL-1 can induce stabilization of KSRP target mRNAs, including that of IL-6 (14, 15), by reducing interaction of KSRP with the ARE presumably as a result of KSRP phosphorylation by p38 MAP kinase (10).IL-6, originally cloned as 26-kDa protein (16), IFN-␤2 (17), and BSF-2 (18), is a pleiotropic cytokine with important roles in inflammation, immune regulation, oncogenesis, and other physiological and pathological processes. Accordingly, interfering with IL-6 action is the aim of therapeutic strategies (19,20). IL-6 is induced in various cell types by a plethora of activators. Among the strongest and first identified are the proinflammatory cytokines tumor necrosis factor (TNF) (21) and IL-1 (22). Expression of IL-6 is controlled by transcriptional and post-transcriptional mechanisms. The latter involve AREs and a putative stem-loop structure that cause rapid degradation of the mRNA (23). Activators like IL-1 and lipopolysaccharide induce IL-6 mRNA stabilization through p38 MAPK/MK2 signaling (14, 24). IL-6 expression is also controlled by miRNAs (25,26).Our recent data showed that, in addition to stabilizing mRNAs, IL-1 can activate translation of mRNAs, including that of . We now provide evidence that repressed basal translation of IL-6 and a group of other mRNAs depends on KSRP. Interaction of KSRP with the IL-6 ARE is direct and is decreased in response to IL-1, suggesting a novel, miRNA-independent function for KSRP in translation.

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Section: Discussioncontrasting

confidence: 59%

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confidence: 99%

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Interleukin-1 Activates Synthesis of Interleukin-6 by Interfering with a KH-type Splicing Regulatory Protein (KSRP)-dependent Translational Silencing Mechanism

Dhamija

Kuehne

Winzen

et al. 2011

Journal of Biological Chemistry

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“…Untemplated nucleotide additions to sRNAs have been observed in animals, plants, and now algae (19,36,(39)(40)(41)(42). The role of these modifications is poorly understood but our findings and those of others (18,36,39) suggest that they may influence the stability and/or the function of mature small RNAs. MUT68 depletion resulted in a defect in 3′ terminal uridylation of certain small RNAs and an alteration in their steady-state levels.…”

Section: Discussionmentioning

confidence: 53%

“…This leads to precursor RNA degradation and downregulation of the let-7 miRNA. In contrast, terminal uridylation of mature miR-26 in mammalian cells appears to impart functional differences that attenuate miRNA-targeted repression without obvious changes in miRNA steady-state levels (18). In A. thaliana, 3′ end uridylation has been postulated, although not demonstrated yet, to stimulate the decay of small RNAs (19,20).…”

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Uridylation of mature miRNAs and siRNAs by the MUT68 nucleotidyltransferase promotes their degradation in Chlamydomonas

Ibrahim

Rymarquis

Kim

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

127

185

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Regulation of gene expression by small RNAs (∼20-30 nucleotides in length) plays an essential role in developmental pathways and defense responses against genomic parasites in eukaryotes. MicroRNAs (miRNAs) and small interfering RNAs (siRNAs) commonly direct the inactivation of cognate sequences through a variety of mechanisms, including RNA degradation, translation inhibition, and transcriptional repression. Recent studies have provided considerable insight into the biogenesis and the mode of action of miRNAs and siRNAs. However, relatively little is known about mechanisms of quality control and small RNA decay in RNA interference (RNAi) pathways. Here we show that deletion of MUT68, encoding a terminal nucleotidyltransferase in the alga Chlamydomonas reinhardtii, results in elevated miRNA and siRNA levels. We found that MUT68 plays a role in the untemplated uridylation of the 3′ ends of small RNAs in vivo and stimulates their degradation by the RRP6 exosome subunit in vitro. Moreover, RRP6 depletion also leads to accumulation of small RNAs in vivo. We propose that MUT68 and RRP6 cooperate in the degradation of mature miRNAs and siRNAs, as a quality control mechanism to eliminate dysfunctional or damaged small RNA molecules.exosome | RNA interference | miRNA quality control

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Identification and Expression Profiling of Small RNA Populations Using High‐Throughput Sequencing

Armisen

Shaw

Miska

2011

Tag‐Based Next Generation Sequencing

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Zcchc11-dependent uridylation of microRNA directs cytokine expression

Cited by 279 publications

References 40 publications

Interleukin-1 Activates Synthesis of Interleukin-6 by Interfering with a KH-type Splicing Regulatory Protein (KSRP)-dependent Translational Silencing Mechanism

Interleukin-1 Activates Synthesis of Interleukin-6 by Interfering with a KH-type Splicing Regulatory Protein (KSRP)-dependent Translational Silencing Mechanism

Uridylation of mature miRNAs and siRNAs by the MUT68 nucleotidyltransferase promotes their degradation in Chlamydomonas

Identification and Expression Profiling of Small RNA Populations Using High‐Throughput Sequencing

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