Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins

Bridge, Katherine S.; Shah, Kunal M.; Li, Yigen; Foxler, Daniel E.; Wong, Sybil C K; Miller, Duncan C.; Davidson, Kathryn; Foster, John G.; Rose, Ruth-Sarah; Hodgkinson, Michael R.; Ribeiro, Paulo S.; Aboobaker, A. Aziz; Yashiro, Kenta; Wang, Xiaozhong; Graves, Paul R.; Plevin, Michael J.; Lagos, Dimitrios; Sharp, Tyson V.

doi:10.1016/j.celrep.2017.06.027

Cited by 56 publications

(64 citation statements)

References 46 publications

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“…Previous reports suggest the Ago2‐GW182 interaction is regulated in HeLa cells by phosphorylation of Ago2 at S387 by the kinase Akt (Horman et al , 2013; Bridge et al , 2017). We therefore hypothesised that the NMDAR‐stimulated increase in binding would be mediated by a similar mechanism.…”

Section: Resultsmentioning

confidence: 98%

“…While S387 is situated between the PAZ and MID domains of Ago2, GW182 associates with the PIWI domain towards the C‐terminus of Ago2 (Pfaff et al , 2013), suggesting that phosphorylated S387 is unlikely to contribute to the GW182 binding site directly. A recent study provides an explanation for this by demonstrating that the LIM‐domain protein LIMD1 binds both GW182 and S387‐phosphorylated Ago2 in HeLa cells and stabilises the interaction between Ago2 and GW182 in response to Ago2 phosphorylation (Bridge et al , 2017). Interestingly, this report further suggests that DDX6 is also recruited to Ago2 by S387 phosphorylation, presumably by interacting with GW182 following LIMD1 binding.…”

Section: Discussionmentioning

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: 98%

Section: Discussionmentioning

confidence: 99%

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

et al. 2018

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“…This mode of action will ultimately lead to translation inhibition of Ago1/2 targets (James et al, 2010). A more recent study has determined that the LIM domains of LIMD1 are the interaction surface with TNRC6A (Bridge et al, 2017). Moreover, LIMD1 bridges AGO2 to TNRC6A/miRISC (Bridge et al, 2017).…”

Section: A Parallel Between Gtsf-1 In Animals and Stc1 In Fission Yeastmentioning

confidence: 99%

“…A more recent study has determined that the LIM domains of LIMD1 are the interaction surface with TNRC6A (Bridge et al, 2017). Moreover, LIMD1 bridges AGO2 to TNRC6A/miRISC (Bridge et al, 2017).…”

Section: A Parallel Between Gtsf-1 In Animals and Stc1 In Fission Yeastmentioning

confidence: 99%

GTSF ‐1 is required for formation of a functional RNA ‐dependent RNA Polymerase complex in Caenorhabditis elegans

Almeida

Dietz²,

Redl

et al. 2018

The EMBO Journal

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Argonaute proteins and their associated small RNAs (sRNAs) are evolutionarily conserved regulators of gene expression. Gametocyte-specific factor 1 (Gtsf1) proteins, characterized by two tandem CHHC zinc fingers and an unstructured C-terminal tail, are conserved in animals and have been shown to interact with Piwi clade Argonautes, thereby assisting their activity. We identified the Gtsf1 homolog, named it and characterized it in the context of the sRNA pathways of We report that GTSF-1 is not required for Piwi-mediated gene silencing. Instead, mutants show a striking depletion of 26G-RNAs, a class of endogenous sRNAs, fully phenocopying mutants. We show, both and , that GTSF-1 interacts with RRF-3 via its CHHC zinc fingers. Furthermore, we demonstrate that GTSF-1 is required for the assembly of a larger RRF-3 and DCR-1-containing complex (ERIC), thereby allowing for 26G-RNA generation. We propose that GTSF-1 homologs may act to drive the assembly of larger complexes that act in sRNA production and/or in imposing sRNA-mediated silencing activities.

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“…Interestingly, AGO2‐RV‐NSP1 association was found to be unperturbed in the presence of both single‐stranded RNA‐specific RNase I and double‐stranded RNA‐specific RNase III (Figure b), excluding the possibility of viral RNA scaffold to have a mediating role. AGO2 activity has been reported to be regulated by phosphorylation (Bridge et al, ; Horman et al, ). Phosphorylation of RV‐OSU‐NSP1 by caesin kinase II has also recently been shown to be a prerequisite for NSP1‐βTrCP association (Davis et al, ).…”

Section: Resultsmentioning

confidence: 99%

Biphasic regulation of RNA interference during rotavirus infection by modulation of Argonaute2

Mukhopadhyay

Chanda

Patra

et al. 2019

Cellular Microbiology

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RNA interference (RNAi) is an evolutionary ancient innate immune response in plants, nematodes, and arthropods providing natural protection against viral infection. Viruses have also gained counter‐defensive measures by producing virulence determinants called viral‐suppressors‐of‐RNAi (VSRs). Interestingly, in spite of dominance of interferon‐based immunity over RNAi in somatic cells of higher vertebrates, recent reports are accumulating in favour of retention of the antiviral nature of RNAi in mammalian cells. The present study focuses on the modulation of intracellular RNAi during infection with rotavirus (RV), an enteric virus with double‐stranded RNA genome. Intriguingly, a time point‐dependent bimodal regulation of RNAi was observed in RV‐infected cells, where short interfering RNA (siRNA)‐based RNAi was rendered non‐functional during early hours of infection only to be reinstated fully beyond that early infection stage. Subsequent investigations revealed RV nonstructural protein 1 to serve as a putative VSR by associating with and triggering degradation of Argonaute2 (AGO2), the prime effector of siRNA‐mediated RNAi, via ubiquitin–proteasome pathway. The proviral significance of AGO2 degradation was further confirmed when ectopic overexpression of AGO2 significantly reduced RV infection. Cumulatively, the current study presents a unique modulation of host RNAi during RV infection, highlighting the importance of antiviral RNAi in mammalian cells.

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Argonaute Utilization for miRNA Silencing Is Determined by Phosphorylation-Dependent Recruitment of LIM-Domain-Containing Proteins

Cited by 56 publications

References 46 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

GTSF ‐1 is required for formation of a functional RNA ‐dependent RNA Polymerase complex in Caenorhabditis elegans

Biphasic regulation of RNA interference during rotavirus infection by modulation of Argonaute2

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