Towards a molecular understanding of microRNA-mediated gene silencing

Jonas, Steven; Izaurralde, Elisa

doi:10.1038/nrg3965

Cited by 1,593 publications

(1,340 citation statements)

References 116 publications

(392 reference statements)

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“…To investigate the regulation of RISC in response to NMDAR stimulation, we focussed on the interaction between Ago2 and GW182, because this interaction is a critical regulator of RISC function (Pfaff & Meister, 2013; Jonas & Izaurralde, 2015). Co‐immunoprecipitation of endogenous GW182 with endogenous Ago2 from cultured cortical neurons was significantly increased 10 min after bath application of NMDA (Fig 1A).…”

Section: Resultsmentioning

confidence: 99%

“…Agos interact with numerous proteins that are essential for or modulate their gene silencing activity. In particular, GW182 (also known as TNRC6A) is an evolutionarily conserved component of RISCs and is essential for mediating the gene silencing steps downstream of RISC formation by recruiting additional proteins with relevant scaffolding or enzymatic activities (Pfaff & Meister, 2013; Jonas & Izaurralde, 2015). Importantly, Ago2 can be phosphorylated at a number of residues, some of which have been suggested to regulate RISC activity in non‐neuronal cell lines by controlling Ago2‐RNA or Ago2‐protein interactions (Jee & Lai, 2014).…”

Section: Introductionmentioning

confidence: 99%

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NMDAR ‐dependent Argonaute 2 phosphorylation regulates mi RNA activity and dendritic spine plasticity

et al. 2018

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MicroRNAs (miRNAs) repress translation of target mRNAs by associating with Argonaute (Ago) proteins to form the RNA‐induced silencing complex (RISC), underpinning a powerful mechanism for fine‐tuning protein expression. Specific miRNAs are required for NMDA receptor (NMDAR)‐dependent synaptic plasticity by modulating the translation of proteins involved in dendritic spine morphogenesis or synaptic transmission. However, it is unknown how NMDAR stimulation stimulates RISC activity to rapidly repress translation of synaptic proteins. We show that NMDAR stimulation transiently increases Akt‐dependent phosphorylation of Ago2 at S387, which causes an increase in binding to GW182 and a rapid increase in translational repression of LIMK1 via miR‐134. Furthermore, NMDAR‐dependent down‐regulation of endogenous LIMK1 translation in dendrites and dendritic spine shrinkage requires phospho‐regulation of Ago2 at S387. AMPAR trafficking and hippocampal LTD do not involve S387 phosphorylation, defining this mechanism as a specific pathway for structural plasticity. This work defines a novel mechanism for the rapid transduction of NMDAR stimulation into miRNA‐mediated translational repression to control dendritic spine morphology.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NMDAR ‐dependent Argonaute 2 phosphorylation regulates mi RNA activity and dendritic spine plasticity

et al. 2018

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“…One possible model is that the recruitment of the CCR4–NOT complex is sufficient to mediate silencing (Jonas & Izaurralde, 2015). This model is based on the following observations: First, the interaction of GW182 proteins with the CCR4–NOT complex is not only required for degradation but also required for translational repression of miRNA reporters (Braun et al , 2011; Chekulaeva et al , 2011; Fabian et al , 2011; Huntzinger et al , 2013; Zekri et al , 2013; Chen et al , 2014; Mathys et al , 2014).…”

Section: Introductionmentioning

confidence: 99%

mi RISC and the CCR 4– NOT complex silence mRNA targets independently of 43S ribosomal scanning

et al. 2016

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AbstractmiRNAs associate with Argonaute (AGO) proteins to silence the expression of mRNA targets by inhibiting translation and promoting deadenylation, decapping, and mRNA degradation. A current model for silencing suggests that AGOs mediate these effects through the sequential recruitment of GW182 proteins, the CCR4–NOT deadenylase complex and the translational repressor and decapping activator DDX6. An alternative model posits that AGOs repress translation by interfering with eIF4A function during 43S ribosomal scanning and that this mechanism is independent of GW182 and the CCR4–NOT complex in Drosophila melanogaster. Here, we show that miRNAs, AGOs, GW182, the CCR4–NOT complex, and DDX6/Me31B repress and degrade polyadenylated mRNA targets that are translated via scanning‐independent mechanisms in both human and Dm cells. This and additional observations indicate a common mechanism used by these proteins and miRNAs to mediate silencing. This mechanism does not require eIF4A function during ribosomal scanning.

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“…Many RNA-degrading enzymes function in multisubunit complexes, and their enzymatic activity and substrate specificity can be dramatically altered by protein partners [13,86,87]. The predicted involvement of partner molecules – particularly RNA-binding proteins (RBPs) – in controlling NOCT activity is intriguing because such a partner could modulate the specificity and affinity of NOCT for target mRNAs as has been observed for other deadenylases (Fig.…”

Section: Do Noct Protein Partners Control Its Function?mentioning

confidence: 99%

Regulatory roles of vertebrate Nocturnin: insights and remaining mysteries

2018

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Post-transcriptional control of messenger RNA (mRNA) is an important layer of gene regulation that modulates mRNA decay, translation, and localization. Eukaryotic mRNA decay begins with the catalytic removal of the 3′ poly-adenosine tail by deadenylase enzymes. Multiple deadenylases have been identified in vertebrates and are known to have distinct biological roles; among these proteins is Nocturnin, which has been linked to circadian biology, adipogenesis, osteogenesis, and obesity. Multiple studies have investigated Nocturnin’s involvement in these processes; however, a full understanding of its molecular function remains elusive. Recent studies have provided new insights by identifying putative Nocturnin-regulated mRNAs in mice and by determining the structure and regulatory activities of human Nocturnin. This review seeks to integrate these new discoveries into our understanding of Nocturnin’s regulatory functions and highlight the important remaining unanswered questions surrounding its regulation, biochemical activities, protein partners, and target mRNAs.

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Towards a molecular understanding of microRNA-mediated gene silencing

Cited by 1,593 publications

References 116 publications

NMDAR ‐dependent Argonaute 2 phosphorylation regulates mi RNA activity and dendritic spine plasticity

NMDAR ‐dependent Argonaute 2 phosphorylation regulates mi RNA activity and dendritic spine plasticity

mi RISC and the CCR 4– NOT complex silence mRNA targets independently of 43S ribosomal scanning

Regulatory roles of vertebrate Nocturnin: insights and remaining mysteries

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