Disassembly of Exon Junction Complexes by PYM

Gehring, Niels H.; Lamprinaki, Styliani; Kulozik, Andreas E.; Hentze, Matthias W.

doi:10.1016/j.cell.2009.02.042

Cited by 167 publications

(182 citation statements)

References 35 publications

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“…Magoh and Y14 were found predominantly in the lighter mRNPs fractions, and a small proportion also was found within the monosome fractions. This profile is in agreement with the dissociation of EJC cores by translating ribosomes (5). In contrast, eIF4A3 and MLN51 cosedimented with the monosome fractions (40S, 60S, and 80S) but also were enriched in polysome fractions.…”

Section: Mln51 Protein Level Modulates the Translation Efficiency In supporting

confidence: 74%

“…This multiprotein complex is assembled onto mRNA as a consequence of pre-mRNA splicing upstream of exon-exon junctions (3,4). The EJC remains associated with mRNAs and is exported to the cytoplasm until it is stripped off by translating ribosomes (5). Hence, the EJC transmits mRNA history to subsequent posttranscriptional events as a molecular signature of splicing.…”

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confidence: 99%

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EJC core component MLN51 interacts with eIF3 and activates translation

Chazal

Daguenet

Wendling

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The multiprotein exon junction complex (EJC), deposited by the splicing machinery, is an important constituent of messenger ribonucleoprotein particles because it participates to numerous steps of the mRNA lifecycle from splicing to surveillance via nonsense-mediated mRNA decay pathway. By an unknown mechanism, the EJC also stimulates translation efficiency of newly synthesized mRNAs. Here, we show that among the four EJC core components, the RNA-binding protein metastatic lymph node 51 (MLN51) is a translation enhancer. Overexpression of MLN51 preferentially increased the translation of intron-containing reporters via the EJC, whereas silencing MLN51 decreased translation. In addition, modulation of the MLN51 level in cell-free translational extracts confirmed its direct role in protein synthesis. Immunoprecipitations indicated that MLN51 associates with translation-initiating factors and ribosomal subunits, and in vitro binding assays revealed that MLN51, alone or as part of the EJC, interacts directly with the pivotal eukaryotic translation initiation factor eIF3. Taken together, our data define MLN51 as a translation activator linking the EJC and the translation machinery.

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Section: Mln51 Protein Level Modulates the Translation Efficiency In supporting

confidence: 74%

mentioning

confidence: 99%

EJC core component MLN51 interacts with eIF3 and activates translation

Chazal

Daguenet

Wendling

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…The EJC contains a heterotetrameric protein core that includes eIF4AIII, Magoh, Y14, metastatic lymph node 51 (MLN51; also known as Barentsz), and peripheral proteins. The EJC plays various roles in posttranscriptional regulation, including mRNA export from the nucleus, subcellular mRNA localization, translation, and NMD, as reported previously (18,19).EJCs are largely found in CBC-bound mRNA but not in eIF4E-bound mRNA (5), and the deposited EJCs are displaced by a translocating ribosome (20). Accordingly, it is believed that the EJC promotes efficiency of CT rather than ET.…”

mentioning

confidence: 70%

“…EJCs are largely found in CBC-bound mRNA but not in eIF4E-bound mRNA (5), and the deposited EJCs are displaced by a translocating ribosome (20). Accordingly, it is believed that the EJC promotes efficiency of CT rather than ET.…”

Section: Significancementioning

confidence: 99%

eIF4AIII enhances translation of nuclear cap-binding complex–bound mRNAs by promoting disruption of secondary structures in 5′UTR

Choe

Ryu

Park

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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It has long been considered that intron-containing (spliced) mRNAs are translationally more active than intronless mRNAs (identical mRNA not produced by splicing). The splicing-dependent translational enhancement is mediated, in part, by the exon junction complex (EJC). Nonetheless, the molecular mechanism by which each EJC component contributes to the translational enhancement remains unclear. Here, we demonstrate the previously unappreciated role of eukaryotic translation initiation factor 4AIII (eIF4AIII), a component of EJC, in the translation of mRNAs bound by the nuclear cap-binding complex (CBC), a heterodimer of cap-binding protein 80 (CBP80) and CBP20. eIF4AIII is recruited to the 5′-end of mRNAs bound by the CBC by direct interaction with the CBCdependent translation initiation factor (CTIF); this recruitment of eIF4AIII is independent of the presence of introns (deposited EJCs after splicing). Polysome fractionation, tethering experiments, and in vitro reconstitution experiments using recombinant proteins show that eIF4AIII promotes efficient unwinding of secondary structures in 5′UTR, and consequently enhances CBC-dependent translation in vivo and in vitro. Therefore, our data provide evidence that eIF4AIII is a specific translation initiation factor for CBC-dependent translation.eIF4AIII | cap-binding complex | translation | CTIF | nonsense-mediated mRNA decay I n mammalian cells, translation initiation is driven by two major cap-binding proteins (CBPs). One is the nuclear cap-binding complex (CBC), which is a heterodimer of nuclear CBP80 and CBP20 (CBP80/20) (1), and the other is the eukaryotic translation initiation factor (eIF) 4E, which is a major cytoplasmic CBP (2). The CBC binds the 5′-cap structure of a newly synthesized mRNA in the nucleus and then directly interacts with an eIF4G-like scaffold protein called CBP80/20-dependent translation initiation factor (CTIF) (3). Because CTIF is mostly present on the cytoplasmic side of the nuclear envelope and is found in the nucleus (3), the interaction between the CBC and CTIF may occur either in the nucleus or during mRNA export through the nuclear pore complex. In the cytoplasm, at the 5′-end of mRNA, the CBC-CTIF complex recruits the eIF3 complex (4) and then the 40S small subunit of the ribosome, thereby directing the socalled "first" (or pioneer) round of translation (1).Translation of a CBC-bound mRNA precedes that of the eIF4E-bound mRNA, because the CBC-bound mRNA is a precursor form of the eIF4E-bound mRNA (5). The timing of the replacement of the CBC by eIF4E has not yet been elucidated; however, it is known that the replacement is mediated by the action of importin α/β in a translation-independent manner (6). The replaced eIF4E at the 5′-end of mRNA recruits a scaffold protein, eIF4GI or eIF4GII, which recruits eIF3 and eIF4AI/II and, eventually, the 40S ribosomal subunit. Then, the recruited 40S subunit scans the mRNA until it reaches the authentic translation initiation codon AUG. Efficient ribosome scanning requires either eIF4AI or e...

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“…How this regulation occurs, and whether eIF4AIII is required for this discrimination, is not known. Removal of the EJC from mRNA is thought to require additional factors and ongoing translation 70 .…”

Section: Atp Ground Statementioning

confidence: 99%

From unwinding to clamping — the DEAD box RNA helicase family

Linder

Jankowsky

2011

Nat Rev Mol Cell Biol

956

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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Disassembly of Exon Junction Complexes by PYM

Cited by 167 publications

References 35 publications

EJC core component MLN51 interacts with eIF3 and activates translation

EJC core component MLN51 interacts with eIF3 and activates translation

eIF4AIII enhances translation of nuclear cap-binding complex–bound mRNAs by promoting disruption of secondary structures in 5′UTR

From unwinding to clamping — the DEAD box RNA helicase family

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