Mammalian GW220/TNGW1 is essential for the formation of GW/P bodies containing miRISC

Castilla-Llorente, Virginia; Spraggon, Lee; Okamura, Miwako; Naseeruddin, Saif; Adamow, Matthew; Qamar, Sarah; Liu, Jidong

doi:10.1083/jcb.201201153

Cited by 14 publications

(12 citation statements)

References 68 publications

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“…Anti-GW220 antibody only detects a subset of the P-bodies containing TNRC6 family proteins ( Fig. 5B, control KD), consistent with the observation that not all P-bodies contain GW220 protein (Castilla-Llorente et al 2012). It was striking that P-bodies (with and without GW220) were barely detected when Pan3S was depleted ( Fig.…”

Section: Pan3l and Pan3s Have Different Roles In Relation To P-bodiessupporting

confidence: 85%

“…Thus, it is possible that when the functions of the two human Pan3 isoforms in mRNA deadenylation and decay (see below) are disrupted, it may compromise proper cytoplasmic mRNP remodeling as manifested by changes in P-body dynamics and constituents. Indeed, a recent study using human U2OS cells identified a distinct subclass of P-bodies (GW/P-bodies) containing a unique GW protein splice variant GW220 (Castilla-Llorente et al 2012). This raised an interesting question as to whether the individual Pan3 isoforms have distinct roles in GW/P-body formation.…”

Section: Pan3l and Pan3s Have Different Roles In Relation To P-bodiesmentioning

confidence: 99%

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Antagonistic actions of two human Pan3 isoforms on global mRNA turnover

Chen

Zhang

et al. 2017

RNA

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Deadenylation is a fundamental process that regulates eukaryotic gene expression. Mammalian deadenylation exhibits biphasic kinetics, with the Pan2-Pan3 and Ccr4-Caf1 deadenylase complexes mediating the first and second phase, respectively; however, the significance of the biphasic nature of deadenylation in mRNA turnover remains unclear. In this study, we discovered that two distinct isoforms of human Pan3 display opposing properties necessary for coordinating the two phases of deadenylation. The shorter isoform (Pan3S) interacts more strongly with PABP than the longer isoform (Pan3L) does. Pan2 deadenylase activity is enhanced by Pan3S but suppressed by Pan3L. Knocking down individual Pan3 isoforms has opposing effects on the global poly(A) tail length profile, P-body formation, and different mRNA decay pathways. Transcriptome-wide analysis of Pan3 knockdown effects on mRNA turnover shows that depleting either Pan3 isoform causes profound and extensive changes in mRNA stability globally. These results reveal a new fundamental step governing mammalian mRNA metabolism. We propose that the first phase of deadenylation, coordinated through the interplay among the two Pan3 isoforms, Pan2, and PABP, represents a cytoplasmic mRNA maturation step important for proper mRNA turnover.

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Section: Pan3l and Pan3s Have Different Roles In Relation To P-bodiessupporting

confidence: 85%

Section: Pan3l and Pan3s Have Different Roles In Relation To P-bodiesmentioning

confidence: 99%

Antagonistic actions of two human Pan3 isoforms on global mRNA turnover

Chen

Zhang

et al. 2017

RNA

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“…4b). We infer that this may reflect the recruitment of ectopic and endogenous Ago proteins into aggregates 30 , whose loading potential and stability control might be altered. We therefore concentrated our further studies on endogenous mAgo2.…”

Section: Resultsmentioning

confidence: 98%

Homeostatic control of Argonaute stability by microRNA availability

Smibert

Yang

Azzam

et al. 2013

Nat Struct Mol Biol

135

121

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Homeostatic mechanisms regulate the abundance of many small RNA components. We used Drosophila and mammalian systems to demonstrate a conserved homeostatic system in which the status of miRNA biogenesis controls Argonaute protein stability. Clonal analyses of multiple mutants of core Drosophila miRNA factors revealed that stability of the miRNA effector AGO1 is dependent on miRNA biogenesis. Reciprocally, ectopic transcription of miRNAs within in vivo clones induced accumulation of AGO1, as did genetic interference with the ubiquitin-proteasome system. In mammals, we found that the stability of mAgo2 declined in Dicer knockout cells, and was rescued by proteasome blockade or introduction of either Dicer plasmid or Dicer-independent miRNA constructs. Importantly, Dicer-dependent miRNA constructs generated pre-miRNAs that bind Ago2, but did not rescue Ago2 stability. We conclude that Argonaute levels are finely tuned by cellular availability of mature miRNAs and the ubiquitin-proteasome system.

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“…Based on the RPF reductions attributable to these two repression modes, their relative contributions to repression are then calculated (Figure S2). Of the two modes, mRNA degradation dominates in U2OS cells (Figure 1B), despite the presence of a P-body subtype reported to impart increased translational repression (Castilla-Llorente et al, 2012). …”

Section: Resultsmentioning

confidence: 99%

mRNA Destabilization Is the Dominant Effect of Mammalian MicroRNAs by the Time Substantial Repression Ensues

et al. 2014

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Summary MicroRNAs (miRNAs) regulate target mRNAs through a combination of translational repression and mRNA destabilization, with mRNA destabilization dominating at steady state in the few contexts examined globally. Here, we extend the global steady-state measurements to additional mammalian contexts and find that regardless of the miRNA, cell type, growth condition, or translational state, mRNA destabilization explains most (66% to >90%) miRNA-mediated repression. We also determine the relative dynamics of translational repression and mRNA destabilization for endogenous mRNAs as a miRNA is induced. Although translational repression occurs rapidly, its effect is relatively weak, such that by the time consequential repression ensues, the effect of mRNA destabilization dominates. These results imply that consequential miRNA-mediated repression is largely irreversible and provide other insights into the nature of miRNA-mediated regulation. They also simplify future studies, dramatically extending the known contexts and time points for which monitoring mRNA changes captures most of the direct miRNA effects.

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Mammalian GW220/TNGW1 is essential for the formation of GW/P bodies containing miRISC

Abstract: Localization of the miRNA-induced silencing complex to GW/P bodies by GW220/TNGW1 may regulate the fate of target mRNAs.

Cited by 14 publications

References 68 publications

Antagonistic actions of two human Pan3 isoforms on global mRNA turnover

Antagonistic actions of two human Pan3 isoforms on global mRNA turnover

Homeostatic control of Argonaute stability by microRNA availability

mRNA Destabilization Is the Dominant Effect of Mammalian MicroRNAs by the Time Substantial Repression Ensues

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