The mRNA Export Factor Gle1 and Inositol Hexakisphosphate Regulate Distinct Stages of Translation

Bolger, Timothy A.; Folkmann, Andrew W.; Tran, Elizabeth; Wente, Susan R.

doi:10.1016/j.cell.2008.06.027

Cited by 139 publications

(194 citation statements)

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“…Dbp5 (DDX19 and DDX25 in vertebrates) represents a furthe r emerging paradigm of how DEAD box proteins are regulated: through local activation. It interacts with the transcription machinery and with nascent RNPs 74,75 to mediate mRNA export from the nucleus 110,111 , and it has also been implicated in the termination of translation 112,113 . Although it is not known whether Dbp5 remains bound to mRNAs from transcription to export, as eIF4AIII does, elegant studies have demonstrated that Dbp5 activity must be highly localized during mRNA export 114,115 .…”

Section: Nuclear Specklesmentioning

confidence: 99%

From unwinding to clamping — the DEAD box RNA helicase family

Linder

Jankowsky

2011

Nat Rev Mol Cell Biol

918

1,069

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Nearly all aspects of RNA metabolism, from transcription and translation to mRNA decay, involve RNA helicases, which are enzymes that use ATP to bind or remodel RNA and RNA-protein complexes (ribonucleoprotein (RNP) complexes) 1 . RNA helicases are found in all three domains of life, and many viruses also encode one or more of these proteins 2,3 . Together with the structurally related DNA helicases that function in replication, recombination and repair, the RNA helicases are classified into superfamilies and families, based on sequence and structural features 3,4 . DEAD box proteins form the largest helicase family, with 37 members in humans and 26 in Saccharomyces cerevisiae 3 , and are characterized by the presence of an Asp-Glu-Ala-Asp (DEAD) motif.DEAD box helicases have central and, in many cases, essential physiological roles in cellular RNA metabolism 5 (FIG. 1). The proteins generally function as part of larger multicomponent assemblies, such as the spliceosom e or the eukaryotic translation initiation machinery 6 . Mutations and deregulation of several DEAD box proteins have been linked to disease states, including cancer 7 . Although all DEAD box proteins contain a structurally highly conserved core with conserved ATP-binding and RNA-binding sites, different proteins have been associated with diverse and seemingly unrelated functions, including the disassembly of RNPs, chaperoning during RNA folding and even stabil ization of protein complexes on RNA 5,6 . How these highly conserved proteins fulfil such an array of different functions has been a long-standing question.Research has now started to illuminate the molecular basis for this functional diversity. In this Review, we summarize how structural data, together with biochemical and biophysical studies, have revealed unexpected modes by which these proteins function. We also discuss how novel molecular and cell biological approaches have better defined the cellular roles of DEAD box helicases. We outline our current view on common structural and mechan istic themes that have emerged, and on physical models of how these 'unusual' RNA helicases work.Structures of DEAD box RNA helicases A number of structural studies have universally shown that members of the DEAD box family contain a highly conserved helicase core that harbours the binding sites for ATP and RNA 3,4,8 . The core is surrounded by variable auxiliary domains, which are thought to be critical for the diverse functions of these enzymes.Structure of the helicase core. DEAD box proteins belong to helicase superfamily 2 (SF2) 2 . Similarly to all SF2 helicases, DEAD box proteins are built around a highly conserved helicase core of two virtually identical domains that resemble the bacterial recombination protein recombinase A (RecA) 3,4,8 (FIG. 2a,b). Within this helicase core, at least 12 characteristic sequence motifs are located at conserved positions (FIG. 2a,b). Some of these motifs are conserved across the entire SF2 family, whereas others are found only in the DEAD box family 3 ....

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Section: Nuclear Specklesmentioning

confidence: 99%

From unwinding to clamping — the DEAD box RNA helicase family

Linder

Jankowsky

2011

Nat Rev Mol Cell Biol

918

1,069

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“…T h e GLE1 gene is highly conserved between species (Alcazar-Roman et al, , Bolger et al, 2008. In humans, it encodes two protein coding isoforms; GLE1A and GLE1B.…”

Section: Introductionmentioning

confidence: 99%

“…It has been reported that Gle1 has other functionally distinct roles in translation. Studies in yeast suggest that it is involved in translation termination through IP 6 -dependent Dbp5 activation, and in translation initiation in an IP 6 /Dbp5-independent manner (Bolger et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo

et al. 2016

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-GLE1 mutations cause lethal congenital contracture syndrome 1 (LCCS1), a severe autosomal recessive fetal motor neuron disease, and more recently have been associated with amyotrophic lateral sclerosis (ALS). The gene encodes a highly conserved protein with an essential role in mRNA export. The mechanism linking Gle1 function to motor neuron degeneration in humans has not been elucidated, but increasing evidence implicates abnormal RNA processing as a key event in the pathogenesis of several motor neuron

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“…Moreover, the extent of functional connections between mRNA export and translation is unknown. Intriguingly, we and others have shown that Dbp5, Gle1, and IP 6 have roles in translation independent from their roles in mRNA export (32,33). Functionally, each of these factors is required for efficient translation termination.…”

mentioning

confidence: 99%

Control of mRNA Export and Translation Termination by Inositol Hexakisphosphate Requires Specific Interaction with Gle1

Alcázar-Román

Bolger

Wente

2010

Journal of Biological Chemistry

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The unidirectional translocation of messenger RNA (mRNA) through the aqueous channel of the nuclear pore complex (NPC) is mediated by interactions between soluble mRNA export factors and distinct binding sites on the NPC. At the cytoplasmic side of the NPC, the conserved mRNA export factors Gle1 and inositol hexakisphosphate (IP 6 ) play an essential role in mRNA export by activating the ATPase activity of the DEAD-box protein Dbp5, promoting localized messenger ribonucleoprotein complex remodeling, and ensuring the directionality of the export process. In addition, Dbp5, Gle1, and IP 6 are also required for proper translation termination. However, the specificity of the IP 6 -Gle1 interaction in vivo is unknown. Here, we characterize the biochemical interaction between Gle1 and IP 6 and the relationship to Dbp5 binding and stimulation. We identify Gle1 residues required for IP 6 binding and show that these residues are needed for IP 6 -dependent Dbp5 stimulation in vitro. Furthermore, we demonstrate that Gle1 is the primary target of IP 6 for both mRNA export and translation termination in vivo. In Saccharomyces cerevisiae cells, the IP 6 -binding mutants recapitulate all of the mRNA export and translation termination defects found in mutants depleted of IP 6 . We conclude that Gle1 specifically binds IP 6 and that this interaction is required for the full potentiation of Dbp5 ATPase activity during both mRNA export and translation termination.Directional transport of mRNA from the nucleus to the cytoplasm is a highly orchestrated process that bridges nuclear mRNA processing events to protein synthesis in the cytoplasm and thus represents a central step in the regulation of gene expression (1-4). Properly capped, spliced, and polyadenylated mRNAs and their associated RNA-binding proteins constitute mature messenger ribonucleoprotein particles (mRNPs). 4 Of importance for nuclear export, soluble mRNA export factors associate with mRNAs throughout this maturation process, some serving dual roles of mRNA processing and transport regulators (5-8). Export requires targeting to and translocation through NPCs, large hetero-oligomeric structures embedded in nuclear envelope pores. The conserved Saccharomyces cerevisiae Mex67/Mtr2 heterodimer (vertebrate TAP/p15 or NXF1/NXT1) is thought to be the major mRNA export receptor, directly binding the mRNP in the nucleus and facilitating NPC docking and translocation by interaction with NPC proteins (Nups) (1, 9, 10). Mex67-Mtr2 interacts preferentially with phenylalanine-glycine repeats found in Nup domains positioned on the nuclear NPC face and within the central NPC channel (11,12).In addition to critical interactions between Mex67-Mtr2 and phenylalanine-glycine repeat domains in the NPC, directional mRNP export is coincident with altered protein-protein and protein-RNA interactions in the mRNP complex (13). For example, Mex67 and the nuclear poly(A) ϩ -binding protein Nab2 are removed from the mRNP during or after the terminal NPC export step (14, 15). Key factors that med...

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The mRNA Export Factor Gle1 and Inositol Hexakisphosphate Regulate Distinct Stages of Translation

Cited by 139 publications

References 46 publications

From unwinding to clamping — the DEAD box RNA helicase family

From unwinding to clamping — the DEAD box RNA helicase family

Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo

Control of mRNA Export and Translation Termination by Inositol Hexakisphosphate Requires Specific Interaction with Gle1

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