EJC core component MLN51 interacts with eIF3 and activates translation

Chazal, Pierre-Etienne; Daguenet, Élisabeth; Wendling, Corinne; Ulryck, Nathalie; Tomasetto, Catherine; Sargueil, Bruno; Hir, Hervé Le

doi:10.1073/pnas.1218732110

Cited by 64 publications

(60 citation statements)

References 41 publications

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“…The EJC also promotes NMD and translation of mRNA (58,76). However, we found no effect of CDK12 depletion on these processes (data not presented).…”

Section: Discussionmentioning

confidence: 52%

Cyclin-Dependent Kinase 12 Increases 3′ End Processing of Growth Factor-Induced c-FOS Transcripts

Eifler

Shao

Bartholomeeusen

et al. 2015

Molecular and Cellular Biology

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Transcriptional cyclin-dependent kinases (CDKs) regulate RNA polymerase II initiation and elongation as well as cotranscriptional mRNA processing. In this report, we describe an important role for CDK12 in the epidermal growth factor (EGF)-induced c-FOS proto-oncogene expression in mammalian cells. This kinase was found in the exon junction complexes (EJC) together with SR proteins and was thus recruited to RNA polymerase II. In cells depleted of CDK12 or eukaryotic translation initiation factor 4A3 (eIF4A3) from the EJC, EGF induced fewer c-FOS transcripts. In these cells, phosphorylation of serines at position 2 in the C-terminal domain (CTD) of RNA polymerase II, as well as levels of cleavage-stimulating factor 64 (Cstf64) and 73-kDa subunit of cleavage and polyadenylation specificity factor (CPSF73), was reduced at the c-FOS gene. These effects impaired 3′ end processing of c-FOS transcripts. Mutant CDK12 proteins lacking their Arg-Ser-rich (RS) domain or just the RS domain alone acted as dominant negative proteins. Thus, CDK12 plays an important role in cotranscriptional processing of c-FOS transcripts.

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“…The EJC also promotes NMD and translation of mRNA (58,76). However, we found no effect of CDK12 depletion on these processes (data not presented).…”

Section: Discussionmentioning

confidence: 52%

Cyclin-Dependent Kinase 12 Increases 3′ End Processing of Growth Factor-Induced c-FOS Transcripts

Eifler

Shao

Bartholomeeusen

et al. 2015

Molecular and Cellular Biology

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“…Among the transcripts up-regulated is the mRNA encoding Casc3 (also known as Btz or MLN51) which is a component of the exon junction complex (EJC) assembled by the spliceosome on exon-exon boundaries after intron excision (Le Hir et al 2000a,b). Beyond its function in quality control as part of the EJC, Casc3 has recently also been shown to enhance translation efficiency (Chazal et al 2013). Sf1 and U2af1 are part of the spliceosomal E complex and bind to introns early during the splice cycle to mark the branch point and the 3 ′ splice site, respectively (Wahl et al 2009).…”

Section: Discussionmentioning

confidence: 99%

Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation

Saal

Briese

Kneitz

et al. 2014

RNA

111

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Neuronal function critically depends on coordinated subcellular distribution of mRNAs. Disturbed mRNA processing and axonal transport has been found in spinal muscular atrophy and could be causative for dysfunction and degeneration of motoneurons. Despite the advances made in characterizing the transport mechanisms of several axonal mRNAs, an unbiased approach to identify the axonal repertoire of mRNAs in healthy and degenerating motoneurons has been lacking. Here we used compartmentalized microfluidic chambers to investigate the somatodendritic and axonal mRNA content of cultured motoneurons by microarray analysis. In axons, transcripts related to protein synthesis and energy production were enriched relative to the somatodendritic compartment. Knockdown of Smn, the protein deficient in spinal muscular atrophy, produced a large number of transcript alterations in both compartments. Transcripts related to immune functions, including MHC class I genes, and with roles in RNA splicing were up-regulated in the somatodendritic compartment. On the axonal side, transcripts associated with axon growth and synaptic activity were down-regulated. These alterations provide evidence that subcellular localization of transcripts with axonal functions as well as regulation of specific transcripts with nonautonomous functions is disturbed in Smn-deficient motoneurons, most likely contributing to the pathophysiology of spinal muscular atrophy.

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“…These observations, together with our present results, show that MLN51 may promote eIF4AIII-mediated unwinding of secondary structures or eIF4AIII-mediated remodeling of the CT complex by enhancing the helicase activity of eIF4AIII. In particular, the MLN51-mediated enhancement of CT via eIF4AIII may be further coordinated by an interaction between MLN51 and eIF3 (47)(48)(49).…”

Section: Discussionmentioning

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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EJC core component MLN51 interacts with eIF3 and activates translation

Cited by 64 publications

References 41 publications

Cyclin-Dependent Kinase 12 Increases 3′ End Processing of Growth Factor-Induced c-FOS Transcripts

Cyclin-Dependent Kinase 12 Increases 3′ End Processing of Growth Factor-Induced c-FOS Transcripts

Subcellular transcriptome alterations in a cell culture model of spinal muscular atrophy point to widespread defects in axonal growth and presynaptic differentiation

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

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