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The exon junction complex as a node of post-transcriptional networks

Nature Reviews Molecular Cell Biology volume 17, pages 41–54 (2016)Cite this article

Subjects

Key Points

  • The EJC is deposited 24 nucleotides upstream of spliced junctions during splicing. It accompanies mRNAs from the nucleus to the cytoplasm, where it is removed by the first round of translation, and recycled back into the nucleus.

  • The core of the EJC consists of four proteins. Structural studies revealed that the DEAD-box RNA helicase eIF4A3 functions as a clamp that binds RNA in a sequence-unspecific manner. MAGOH and Y14 form a heterodimer to lock eIF4A3 onto the mRNA, whereas MLN51 contacts eIF4A3 and the mRNA and provides further stability.

  • The core complex acts as a binding platform for peripheral factors involved in splicing, transport, translation and nonsense-mediated decay (NMD). The composition of peripheral factors depends on the different stages of mRNA processing.

  • The EJC has several functions in regulating different post-transcriptional processes, including splicing, cellular localization, translation and NMD.

  • The EJC is not present at every exon junction, and it does not always bind at the canonical position. This differential loading could impact the composition and functions of different EJCs.

  • The EJC acts as a central node of post-transcriptional gene regulation, and changes in EJC protein expression levels lead to several developmental defects and diseases.

Abstract

The exon junction complex (EJC) is deposited onto mRNAs following splicing and adopts a unique structure, which can both stably bind to mRNAs and function as an anchor for diverse processing factors. Recent findings revealed that in addition to its established roles in nonsense-mediated mRNA decay, the EJC is involved in mRNA splicing, transport and translation. While structural studies have shed light on EJC assembly, transcriptome-wide analyses revealed differential EJC loading at spliced junctions. Thus, the EJC functions as a node of post-transcriptional gene expression networks, the importance of which is being revealed by the discovery of increasing numbers of EJC-related disorders.

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Figure 1: The life cycle of the exon junction complex (EJC).
Figure 2: The function of the exon junction complex (EJC) in splicing and translation.
Figure 3: The functions of the exon junction complex (EJC) in nonsense-mediated mRNA decay (NMD).
Figure 4: Differential exon junction complex (EJC) loading.

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Acknowledgements

Research in the authors' laboratory was supported in part by the Centre National de la Recherche Scientifique and the Institut National de la Santé et de la Recherche Médicale, the Agence Nationale de la Recherche (2011-BLAN-BSV8-01801; 2013-BLAN-BSV8-0023; ANR-14-CE10-0014) and the Labex Memolife.

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  1. Centre national de la recherche scientifique (CNRS), UMR 8197, Paris, F-75005, France.

  2. Institut National de la Santé et de la Recherche Médicale (INSERM), U1024, Paris, F-75005, France.

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  1. Ecole Normale Supérieure, Institut de Biologie de l'ENS (IBENS), Paris, F-75005, France

    Hervé Le Hir, Jérôme Saulière & Zhen Wang

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  1. Hervé Le Hir
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DATABASES

Protein Data Bank

2XB2

4C9B

1RK8

FURTHER INFORMATION

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Glossary

DEAD-box

A protein domain of the conserved amino-acid sequence DEAD (Asp-Glu-Ala-Asp).

MIF4G

Middle domain of eukaryotic initiation factor 4G (eIF4G). This domain is rich in α-helices and can bind to eIF4A and eIF3E within the eIF4F complex.

SR proteins

A conserved protein family involved mainly in RNA splicing. SR proteins contain domains with long repeats of Ser (S) and Arg (R) at the carboxyl terminus, which gives their name. They also contain at least one RRM (RNA-recognition motif) at their amino terminus.

Ribosome scanning

During cap-dependent translation initiation, the 40S small ribosomal unit, together with the tRNA, forms the 43S pre-initiation complex, which 'scans' the mRNA towards the 3′ end from the start codon.

Karyopherin

Group of proteins involved in transporting molecules between the cytoplasm and the nucleus through nuclear pores in eukaryotes.

Weak intron

An intron that contains suboptimal splice sites compared to consensus sequence, leading to less efficient recognition by the spliceosomes.

Cassette exons

Exons that are either included or skipped from the precursor mRNA (pre-mRNA), resulting in the formation of different mRNA isoforms.

Faux 3′ UTR

A model of nonsense-mediated decay (NMD), stating that premature translation termination is inefficient because the terminating ribosomes are far from the poly(A)-binding proteins present at the poly(A) tail, and thus the ribosomes interact instead with up frameshift (UPF) proteins, resulting in NMD.

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Hir, H., Saulière, J. & Wang, Z. The exon junction complex as a node of post-transcriptional networks. Nat Rev Mol Cell Biol 17, 41–54 (2016). https://doi.org/10.1038/nrm.2015.7

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