Scd6 Targets eIF4G to Repress Translation: RGG Motif Proteins as a Class of eIF4G-Binding Proteins

Rajyaguru, Purusharth I; She, Meipei; Parker, Roy

doi:10.1016/j.molcel.2011.11.026

Cited by 126 publications

(216 citation statements)

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“…In yeast, several proteins containing RGG domains were shown to interact with eIF4G and repress translation initiation (39). To determine if the Lsm4 RGG domain could be acting in a similar manner, we conducted a tethering assay with MS2 coat proteinLsm4 fusion proteins and a firefly luciferase reporter mRNA containing a minimal 3= UTR composed of six MS2 coat protein binding sites.…”

Section: The Rgg Domain Of Human Lsm4 Is Required For Pb Formationmentioning

confidence: 99%

The C-Terminal RGG Domain of Human Lsm4 Promotes Processing Body Formation Stimulated by Arginine Dimethylation

Arribas-Layton

Dennis

Bennett

et al. 2016

Molecular and Cellular Biology

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cProcessing bodies (PBs) are conserved cytoplasmic aggregations of translationally repressed mRNAs assembled with mRNA decay factors. The aggregation of mRNA-protein (mRNP) complexes into PBs involves interactions between low-complexity regions of protein components of the mRNPs. In Saccharomyces cerevisiae, the carboxy (C)-terminal Q/N-rich domain of the Lsm4 subunit of the Lsm1-7 complex plays an important role in PB formation, but the C-terminal domain of Lsm4 in most eukaryotes is an RGG domain rather than Q/N rich. Here we show that the Lsm4 RGG domain promotes PB accumulation in human cells and that symmetric dimethylation of arginines within the RGG domain stimulates this process. A mutant Lsm4 protein lacking the RGG domain failed to rescue PB formation in cells depleted of endogenous Lsm4, although this mutant protein retained the ability to assemble with Lsm1-7, associate with decapping factors, and promote mRNA decay and translational repression. Mutation of the symmetrically dimethylated arginines within the RGG domain impaired the ability of Lsm4 to promote PB accumulation. Depletion of PRMT5, the primary protein arginine methyltransferase responsible for symmetric arginine dimethylation, including Lsm4, resulted in loss of PBs. We also uncovered the histone acetyltransferase 1 (HAT1)-RBBP7 lysine acetylase complex as an interaction partner of the Lsm4 RGG domain but found no evidence of a role for this complex in PB metabolism. Together, our findings suggest a stimulatory role for posttranslational modifications in PB accumulation and raise the possibility that mRNP dynamics are posttranslationally regulated. P osttranscriptional gene regulation is critical for maintaining proper cellular function. The combination of proteins interacting with mRNAs making up the messenger ribonucleoproteins (mRNPs) determines the state of the mRNP; whether it is actively translated, targeted for mRNA decay, or stored in a translationally repressed state. These alternative fates of mRNPs can be regulated globally or in an mRNP-specific manner in response to intracellular or extracellular cues (1, 2).Eukaryotic cytoplasmic mRNAs are bound on the 5= cap by the translation initiation complex eIF4F and on the 3= poly(A) tail by poly(A)-binding protein (PABP), which act synergistically to stimulate translation (3). A major pathway of mRNA turnover in eukaryotes initiates by mRNA deadenylation (4, 5). This is followed by decapping by the Dcp2-decapping complex and ultimately 5=-to-3= exonucleolytic decay by Xrn1 (6). The Lsm1-7 complex associates with its cofactor Pat1 (known as PatL1 in humans) and the 3= ends of deadenylated mRNAs and promotes decapping by a mechanism that is not fully understood but involves the association of Lsm1-7-Pat1 with decapping enhancers (7-11).mRNAs that are targeted for deadenylation-initiated mRNA decay can accumulate in the cytoplasm in RNP granules known as processing bodies (PBs) (12). These granules are highly dynamic and sensitive to the level of mRNP intermediates undergoing deadenyla...

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Section: The Rgg Domain Of Human Lsm4 Is Required For Pb Formationmentioning

confidence: 99%

The C-Terminal RGG Domain of Human Lsm4 Promotes Processing Body Formation Stimulated by Arginine Dimethylation

Arribas-Layton

Dennis

Bennett

et al. 2016

Molecular and Cellular Biology

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“…4E-T is another eIF4E-binding protein, which inhibits translation initiation by a less welldefined mechanism (Dostie et al 2000). Furthermore, a class of Saccharomyces cerevisiae RGG-domain proteins associate with eIF4G to represses translation (Rajyaguru et al 2012). Another factor that interferes with cap-dependent translation is 4EHP (also known as eIF4E2).…”

Section: Introductionmentioning

confidence: 99%

Recruitment of the 4EHP-GYF2 cap-binding complex to tetraproline motifs of tristetraprolin promotes repression and degradation of mRNAs with AU-rich elements

Olsen

Webb

et al. 2016

RNA

101

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The zinc finger protein tristetraprolin (TTP) promotes translation repression and degradation of mRNAs containing AU-rich elements (AREs). Although much attention has been directed toward understanding the decay process and machinery involved, the translation repression role of TTP has remained poorly understood. Here we identify the cap-binding translation repression 4EHP-GYF2 complex as a cofactor of TTP. Immunoprecipitation and in vitro pull-down assays demonstrate that TTP associates with the 4EHP-GYF2 complex via direct interaction with GYF2, and mutational analyses show that this interaction occurs via conserved tetraproline motifs of TTP. Mutant TTP with diminished 4EHP-GYF2 binding is impaired in its ability to repress a luciferase reporter ARE-mRNA. 4EHP knockout mouse embryonic fibroblasts (MEFs) display increased induction and slower turnover of TTP-target mRNAs as compared to wild-type MEFs. Our work highlights the function of the conserved tetraproline motifs of TTP and identifies 4EHP-GYF2 as a cofactor in translational repression and mRNA decay by TTP.

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“…17 Our results demonstrate that Scd6 prevents the formation of 48S preinitiation complex by binding eIF4G through its RGG motif. 1 The repressed mRNAs have an intact cap-binding complex consisting of eIF4E-4G-4A and Pab1. Such a mechanism has implications in stable storage of mRNA, discussed later in this article.…”

Section: Mrnps Poised For Re-entry To Translationmentioning

confidence: 99%

“…Moreover, initial mapping of the interaction domains suggest that these proteins can interact with different parts of the eIF4G molecule. 1 This suggests three different models for how RGG motif proteins might be interacting with eIF4G and its implication on global cellular translation (Fig. 1) 47 Interestingly, the Lsm domain of Scd6 is responsible for the interaction with Dcp2, 45 whereas RGG motif domain interacts with eIF4G.…”

Section: Why Do So Many Rgg Motifmentioning

confidence: 99%

“…1) 47 Interestingly, the Lsm domain of Scd6 is responsible for the interaction with Dcp2, 45 whereas RGG motif domain interacts with eIF4G. 1 There are two non-mutually exclusive possibilities for how Scd6 might stimulate decapping. In one model, Scd6 would initially repress translation of an mRNA by binding to eIF4G followed by recruitment of Dcp2, which would then enhance loss of eIF4E, leading to mRNA decapping.…”

Section: Why Do So Many Rgg Motifmentioning

confidence: 99%

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RGG motif proteins: Modulators of mRNA functional states

Rajyaguru

Parker

2012

Cell Cycle

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Scd6 Targets eIF4G to Repress Translation: RGG Motif Proteins as a Class of eIF4G-Binding Proteins

Cited by 126 publications

References 50 publications

The C-Terminal RGG Domain of Human Lsm4 Promotes Processing Body Formation Stimulated by Arginine Dimethylation

The C-Terminal RGG Domain of Human Lsm4 Promotes Processing Body Formation Stimulated by Arginine Dimethylation

Recruitment of the 4EHP-GYF2 cap-binding complex to tetraproline motifs of tristetraprolin promotes repression and degradation of mRNAs with AU-rich elements

RGG motif proteins: Modulators of mRNA functional states

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