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

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

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.

Accession codes

Accessions

Protein Data Bank

References

  1. 1

    Le Hir, H., Nott, A. & Moore, M. J. How introns influence and enhance eukaryotic gene expression. Trends Biochem. Sci. 28, 215–220 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. 2

    Maquat, L. E. When cells stop making sense: effects of nonsense codons on RNA metabolism in vertebrate cells. RNA 1, 453–465 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. 3

    Hentze, M. W. & Kulozik, A. E. A perfect message: RNA surveillance and nonsense-mediated decay. Cell 96, 307–310 (1999).

    CAS  PubMed  Google Scholar 

  4. 4

    Shyu, A. B. & Wilkinson, M. F. The double lives of shuttling mRNA binding proteins. Cell 102, 135–138 (2000).

    CAS  PubMed  Google Scholar 

  5. 5

    Kervestin, S. & Jacobson, A. NMD: a multifaceted response to premature translational termination. Nat. Rev. Mol. Cell Biol. 13, 700–712 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6

    Schweingruber, C., Rufener, S. C., Zund, D., Yamashita, A. & Muhlemann, O. Nonsense-mediated mRNA decay — mechanisms of substrate mRNA recognition and degradation in mammalian cells. Biochim. Biophys. Acta 1829, 612–623 (2013).

    CAS  Google Scholar 

  7. 7

    Popp, M. W. & Maquat, L. E. Organizing principles of mammalian nonsense-mediated mRNA decay. Annu. Rev. Genet. 47, 139–165 (2013). References 5–7 provided the first evidence of splicing-dependent NMD in mammals.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. 8

    Cheng, J., Belgrader, P., Zhou, X. & Maquat, L. E. Introns are cis effectors of the nonsense-codon-mediated reduction in nuclear mRNA abundance. Mol. Cell. Biol. 14, 6317–6325 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Carter, M. S., Li, S. & Wilkinson, M. F. A splicing-dependent regulatory mechanism that detects translation signals. EMBO J. 15, 5965–5975 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 10

    Thermann, R. et al. Binary specification of nonsense codons by splicing and cytoplasmic translation. EMBO J. 17, 3484–3494 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11

    Zhang, J., Sun, X., Qian, Y., LaDuca, J. P. & Maquat, L. E. At least one intron is required for the nonsense-mediated decay of triosephosphate isomerase mRNA: a possible link between nuclear splicing and cytoplasmic translation. Mol. Cell. Biol. 18, 5272–5283 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12

    Nagy, E. & Maquat, L. E. A rule for termination-codon position within intron-containing genes: when nonsense affects RNA abundance. Trends Biochem. Sci. 23, 198–199 (1998).

    CAS  Google Scholar 

  13. 13

    Le Hir, H., Izaurralde, E., Maquat, L. E. & Moore, M. J. The spliceosome deposits multiple proteins 20–24 nucleotides upstream of mRNA exon–exon junctions. EMBO J. 19, 6860–6869 (2000). This study was the first to identify the EJCs, which are deposited following splicing 24 nt upstream of the spliced junctions.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. 14

    Kataoka, N. et al. Pre-mRNA splicing imprints mRNA in the nucleus with a novel RNA-binding protein that persists in the cytoplasm. Mol. Cell 6, 673–682 (2000).

    CAS  PubMed  Google Scholar 

  15. 15

    Le Hir, H., Gatfield, D., Izaurralde, E. & Moore, M. J. The exon–exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay. EMBO J. 20, 4987–4997 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Luo, M. L. et al. Pre-mRNA splicing and mRNA export linked by direct interactions between UAP56 and Aly. Nature 413, 644–647 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17

    Kim, V. N. et al. The Y14 protein communicates to the cytoplasm the position of exon–exon junctions. EMBO J. 20, 2062–2068 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Lejeune, F., Ishigaki, Y., Li, X. & Maquat, L. E. The exon junction complex is detected on CBP80-bound but not eIF4E-bound mRNA in mammalian cells: dynamics of mRNP remodeling. EMBO J. 21, 3536–3545 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. 19

    Dostie, J. & Dreyfuss, G. Translation is required to remove Y14 from mRNAs in the cytoplasm. Curr. Biol. 12, 1060–1067 (2002).

    CAS  Article  Google Scholar 

  20. 20

    Gehring, N. H., Lamprinaki, S., Kulozik, A. E. & Hentze, M. W. Disassembly of exon junction complexes by PYM. Cell 137, 536–548 (2009).

    CAS  Article  Google Scholar 

  21. 21

    Lykke-Andersen, J., Shu, M. D. & Steitz, J. A. Communication of the position of exon–exon junctions to the mRNA surveillance machinery by the protein RNPS1. Science 293, 1836–1839 (2001).

    CAS  Google Scholar 

  22. 22

    Kim, V. N., Kataoka, N. & Dreyfuss, G. Role of the nonsense-mediated decay factor hUpf3 in the splicing-dependent exon–exon junction complex. Science 293, 1832–1836 (2001).

    CAS  Google Scholar 

  23. 23

    Wiegand, H. L., Lu, S. & Cullen, B. R. Exon junction complexes mediate the enhancing effect of splicing on mRNA expression. Proc. Natl Acad. Sci. USA 100, 11327–11332 (2003).

    CAS  PubMed  Google Scholar 

  24. 24

    Nott, A., Le Hir, H. & Moore, M. J. Splicing enhances translation in mammalian cells: an additional function of the exon junction complex. Genes Dev. 18, 210–222 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Gehring, N. H., Neu-Yilik, G., Schell, T., Hentze, M. W. & Kulozik, A. E. Y14 and hUpf3b form an NMD-activating complex. Mol. Cell 11, 939–949 (2003).

    CAS  Google Scholar 

  26. 26

    Singh, G., Pratt, G., Yeo, G. W. & Moore, M. J. The clothes make the mRNA: past and present trends in mRNP fashion. Annu. Rev. Biochem. 84, 325–354 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. 27

    Ballut, L. et al. The exon junction core complex is locked onto RNA by inhibition of eIF4AIII ATPase activity. Nat. Struct. Mol. Biol. 12, 861–869 (2005).

    CAS  Google Scholar 

  28. 28

    Tange, T. O., Shibuya, T., Jurica, M. S. & Moore, M. J. Biochemical analysis of the EJC reveals two new factors and a stable tetrameric protein core. RNA 11, 1869–1883 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29

    Fribourg, S., Gatfield, D., Izaurralde, E. & Conti, E. A novel mode of RBD-protein recognition in the Y14–Mago complex. Nat. Struct. Biol. 10, 433–439 (2003).

    CAS  PubMed  Google Scholar 

  30. 30

    Singh, K. K., Wachsmuth, L., Kulozik, A. E. & Gehring, N. H. Two mammalian MAGOH genes contribute to exon junction complex composition and nonsense-mediated decay. RNA Biol. 10, 1291–1298 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31

    Gong, P., Zhao, M. & He, C. Slow co-evolution of the MAGO and Y14 protein families is required for the maintenance of their obligate heterodimerization mode. PLoS ONE 9, e84842 (2014).

    PubMed  PubMed Central  Google Scholar 

  32. 32

    Degot, S. et al. Association of the breast cancer protein MLN51 with the exon junction complex via its speckle localizer and RNA binding module. J. Biol. Chem. 279, 33702–33715 (2004).

    CAS  PubMed  Google Scholar 

  33. 33

    Daguenet, E. et al. Perispeckles are major assembly sites for the exon junction core complex. Mol. Biol. Cell 23, 1765–1782 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34

    Andersen, C. B. et al. Structure of the exon junction core complex with a trapped DEAD-box ATPase bound to RNA. Science 313, 1968–1972 (2006).

    CAS  Google Scholar 

  35. 35

    Bono, F., Ebert, J., Lorentzen, E. & Conti, E. The crystal structure of the exon junction complex reveals how it maintains a stable grip on mRNA. Cell 126, 713–725 (2006). References 34 and 35 show crystal structures of the EJC complex, revealing that the binding of eIF4A3 to mRNAs is stabilized by the Magoh–Y14 heterodimer, and that MLN51 also contacts the mRNA and stabilizes the complex.

    CAS  Google Scholar 

  36. 36

    Linder, P. & Jankowsky, E. From unwinding to clamping — the DEAD box RNA helicase family. Nat. Rev. Mol. Cell Biol. 12, 505–516 (2011).

    CAS  PubMed  Google Scholar 

  37. 37

    Nielsen, K. H. et al. Mechanism of ATP turnover inhibition in the EJC. RNA 15, 67–75 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. 38

    Xiol, J. et al. RNA clamping by Vasa assembles a piRNA amplifier complex on transposon transcripts. Cell 157, 1698–1711 (2014).

    CAS  PubMed  Google Scholar 

  39. 39

    Wahl, M. C., Will, C. L. & Luhrmann, R. The spliceosome: design principles of a dynamic RNP machine. Cell 136, 701–718 (2009).

    CAS  Google Scholar 

  40. 40

    Will, C. L. & Luhrmann, R. Spliceosome structure and function. Cold Spring Harb. Perspect. Biol. 3, a003707 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41

    Bessonov, S., Anokhina, M., Will, C. L., Urlaub, H. & Luhrmann, R. Isolation of an active step I spliceosome and composition of its RNP core. Nature 452, 846–850 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. 42

    Reichert, V. L., Le Hir, H., Jurica, M. S. & Moore, M. J. 5′ exon interactions within the human spliceosome establish a framework for exon junction complex structure and assembly. Genes Dev. 16, 2778–2791 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43

    Makarov, E. M. et al. Small nuclear ribonucleoprotein remodeling during catalytic activation of the spliceosome. Science 298, 2205–2208 (2002).

    CAS  PubMed  Google Scholar 

  44. 44

    Merz, C., Urlaub, H., Will, C. L. & Luhrmann, R. Protein composition of human mRNPs spliced in vitro and differential requirements for mRNP protein recruitment. RNA 13, 116–128 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45

    Zhang, Z. & Krainer, A. R. Splicing remodels messenger ribonucleoprotein architecture via eIF4A3-dependent and -independent recruitment of exon junction complex components. Proc. Natl Acad. Sci. USA 104, 11574–11579 (2007).

    CAS  PubMed  Google Scholar 

  46. 46

    Gehring, N. H., Lamprinaki, S., Hentze, M. W. & Kulozik, A. E. The hierarchy of exon-junction complex assembly by the spliceosome explains key features of mammalian nonsense-mediated mRNA decay. PLoS Biol. 7, e1000120 (2009).

    PubMed  PubMed Central  Google Scholar 

  47. 47

    Shibuya, T., Tange, T. O., Sonenberg, N. & Moore, M. J. eIF4AIII binds spliced mRNA in the exon junction complex and is essential for nonsense-mediated decay. Nat. Struct. Mol. Biol. 11, 346–351 (2004).

    CAS  Google Scholar 

  48. 48

    Yeh, T. C. et al. Splicing factor Cwc22 is required for the function of Prp2 and for the spliceosome to escape from a futile pathway. Mol. Cell. Biol. 31, 43–53 (2011).

    CAS  PubMed  Google Scholar 

  49. 49

    Alexandrov, A., Colognori, D., Shu, M. D. & Steitz, J. A. Human spliceosomal protein CWC22 plays a role in coupling splicing to exon junction complex deposition and nonsense-mediated decay. Proc. Natl Acad. Sci. USA 109, 21313–21318 (2012).

    CAS  PubMed  Google Scholar 

  50. 50

    Barbosa, I. et al. Human CWC22 escorts the helicase eIF4AIII to spliceosomes and promotes exon junction complex assembly. Nat. Struct. Mol. Biol. 19, 983–990 (2012).

    CAS  Google Scholar 

  51. 51

    Steckelberg, A. L., Boehm, V., Gromadzka, A. M. & Gehring, N. H. CWC22 connects pre-mRNA splicing and exon junction complex assembly. Cell Rep. 2, 454–461 (2012). References 49–51 show that CWC22 is a partner of eIF4A3 and facilitates its recruitment to the spliceosome; subsequent EJC assembly requires the dissociation of CWC22.

    CAS  Google Scholar 

  52. 52

    Buchwald, G., Schussler, S., Basquin, C., Le Hir, H. & Conti, E. Crystal structure of the human eIF4AIII–CWC22 complex shows how a DEAD-box protein is inhibited by a MIF4G domain. Proc. Natl Acad. Sci. USA 110, E4611–E4618 (2013).

    CAS  PubMed  Google Scholar 

  53. 53

    Ideue, T., Sasaki, Y. T., Hagiwara, M. & Hirose, T. Introns play an essential role in splicing-dependent formation of the exon junction complex. Genes Dev. 21, 1993–1998 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54

    De, I. et al. The RNA helicase Aquarius exhibits structural adaptations mediating its recruitment to spliceosomes. Nat. Struct. Mol. Biol. 22, 138–144 (2015).

    CAS  PubMed  Google Scholar 

  55. 55

    Tange, T. O., Nott, A. & Moore, M. J. The ever-increasing complexities of the exon junction complex. Curr. Opin. Cell Biol. 16, 279–284 (2004).

    CAS  Google Scholar 

  56. 56

    Custodio, N. et al. In vivo recruitment of exon junction complex proteins to transcription sites in mammalian cell nuclei. RNA 10, 622–633 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57

    Schmidt, U., Richter, K., Berger, A. B. & Lichter, P. In vivo BiFC analysis of Y14 and NXF1 mRNA export complexes: preferential localization within and around SC35 domains. J. Cell Biol. 172, 373–381 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. 58

    Spector, D. L. & Lamond, A. I. Nuclear speckles. Cold Spring Harb. Perspect. Biol. 3, a000646 (2011).

    PubMed  PubMed Central  Google Scholar 

  59. 59

    Blencowe, B. J., Issner, R., Nickerson, J. A. & Sharp, P. A. A coactivator of pre-mRNA splicing. Genes Dev. 12, 996–1009 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60

    Sakashita, E., Tatsumi, S., Werner, D., Endo, H. & Mayeda, A. Human RNPS1 and its associated factors: a versatile alternative pre-mRNA splicing regulator in vivo. Mol. Cell. Biol. 24, 1174–1187 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61

    Singh, K. K. et al. Human SAP18 mediates assembly of a splicing regulatory multiprotein complex via its ubiquitin-like fold. RNA 16, 2442–2454 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62

    Schwerk, C. et al. ASAP, a novel protein complex involved in RNA processing and apoptosis. Mol. Cell. Biol. 23, 2981–2990 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. 63

    Murachelli, A. G., Ebert, J., Basquin, C., Le Hir, H. & Conti, E. The structure of the ASAP core complex reveals the existence of a Pinin-containing PSAP complex. Nat. Struct. Mol. Biol. 19, 378–386 (2012).

    CAS  PubMed  Google Scholar 

  64. 64

    Katahira, J. mRNA export and the TREX complex. Biochim. Biophys. Acta 1819, 507–513 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65

    Kohler, A. & Hurt, E. Exporting RNA from the nucleus to the cytoplasm. Nat. Rev. Mol. Cell Biol. 8, 761–773 (2007).

    PubMed  PubMed Central  Google Scholar 

  66. 66

    Lykke-Andersen, J., Shu, M. D. & Steitz, J. A. Human Upf proteins target an mRNA for nonsense-mediated decay when bound downstream of a termination codon. Cell 103, 1121–1131 (2000).

    CAS  Google Scholar 

  67. 67

    Serin, G., Gersappe, A., Black, J. D., Aronoff, R. & Maquat, L. E. Identification and characterization of human orthologues to Saccharomyces cerevisiae Upf2 protein and Upf3 protein (Caenorhabditis elegans SMG-4). Mol. Cell. Biol. 21, 209–223 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68

    Kunz, J. B., Neu-Yilik, G., Hentze, M. W., Kulozik, A. E. & Gehring, N. H. Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA decay and translation. RNA 12, 1015–1022 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69

    Chamieh, H., Ballut, L., Bonneau, F. & Le Hir, H. NMD factors UPF2 and UPF3 bridge UPF1 to the exon junction complex and stimulate its RNA helicase activity. Nat. Struct. Mol. Biol. 15, 85–93 (2008). This biochemical study shows that the EJC core binds to UPF3B, which serves as a bridge that binds to UPF2 and UPF1, thereby stimulating the RNA helicase activity of UPF1.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70

    Buchwald, G. et al. Insights into the recruitment of the NMD machinery from the crystal structure of a core EJC–UPF3b complex. Proc. Natl Acad. Sci. USA 107, 10050–10055 (2010).

    CAS  PubMed  Google Scholar 

  71. 71

    Kashima, I. et al. Binding of a novel SMG-1–Upf1–eRF1–eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay. Genes Dev. 20, 355–367 (2006). This study defines the stepwise assembly of NMD complexes in human.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72

    Ohnishi, T. et al. Phosphorylation of hUPF1 induces formation of mRNA surveillance complexes containing hSMG-5 and hSMG-7. Mol. Cell 12, 1187–1200 (2003).

    CAS  Google Scholar 

  73. 73

    Kashima, I. et al. SMG6 interacts with the exon junction complex via two conserved EJC-binding motifs (EBMs) required for nonsense-mediated mRNA decay. Genes Dev. 24, 2440–2450 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74

    Gehring, N. H. et al. Exon-junction complex components specify distinct routes of nonsense-mediated mRNA decay with differential cofactor requirements. Mol. Cell 20, 65–75 (2005). This study revealed that UPF2 is required for RNPS1-induced NMD but is dispensable for other EJC core-induced NMD activity.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75

    Singh, N. N., Singh, R. N. & Androphy, E. J. Modulating role of RNA structure in alternative splicing of a critical exon in the spinal muscular atrophy genes. Nucleic Acids Res. 35, 371–389 (2007).

    CAS  PubMed  Google Scholar 

  76. 76

    Ma, X. M., Yoon, S. O., Richardson, C. J., Julich, K. & Blenis, J. SKAR links pre-mRNA splicing to mTOR/S6K1-mediated enhanced translation efficiency of spliced mRNAs. Cell 133, 303–313 (2008).

    CAS  Google Scholar 

  77. 77

    Fonseca, B. D. et al. The ever-evolving role of mTOR in translation. Semin. Cell Dev. Biol. 36, 102–112 (2014).

    CAS  PubMed  Google Scholar 

  78. 78

    Singh, G. et al. The cellular EJC interactome reveals higher-order mRNP structure and an EJC-SR protein nexus. Cell 151, 750–764 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79

    Sauliere, J. et al. CLIP-seq of eIF4AIII reveals transcriptome-wide mapping of the human exon junction complex. Nat. Struct. Mol. Biol. 19, 1124–1131 (2012). Reference 78 and 79 report genome-wide studies that showed that EJC binding is not the same at different splice junctions, both within and between different mRNAs.

    CAS  Google Scholar 

  80. 80

    Long, J. C. & Caceres, J. F. The SR protein family of splicing factors: master regulators of gene expression. Biochem. J. 417, 15–27 (2009).

    CAS  Google Scholar 

  81. 81

    Buxbaum, A. R., Haimovich, G. & Singer, R. H. In the right place at the right time: visualizing and understanding mRNA localization. Nat. Rev. Mol. Cell Biol. 16, 95–109 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. 82

    Bono, F. et al. Molecular insights into the interaction of PYM with the Mago–Y14 core of the exon junction complex. EMBO Rep. 5, 304–310 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. 83

    Diem, M. D., Chan, C. C., Younis, I. & Dreyfuss, G. PYM binds the cytoplasmic exon–junction complex and ribosomes to enhance translation of spliced mRNAs. Nat. Struct. Mol. Biol. 14, 1173–1179 (2007).

    CAS  PubMed  Google Scholar 

  84. 84

    Ghosh, S., Obrdlik, A., Marchand, V. & Ephrussi, A. The EJC binding and dissociating activity of PYM is regulated in Drosophila. PLoS Genet. 10, e1004455 (2014).

    PubMed  PubMed Central  Google Scholar 

  85. 85

    Chazal, P. E. et al. EJC core component MLN51 interacts with eIF3 and activates translation. Proc. Natl Acad. Sci. USA 110, 5903–5908 (2013).

    CAS  PubMed  Google Scholar 

  86. 86

    Mingot, J. M., Kostka, S., Kraft, R., Hartmann, E. & Gorlich, D. Importin 13: a novel mediator of nuclear import and export. EMBO J. 20, 3685–3694 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87

    Bono, F., Cook, A. G., Grunwald, M., Ebert, J. & Conti, E. Nuclear import mechanism of the EJC component Mago–Y14 revealed by structural studies of importin 13. Mol. Cell 37, 211–222 (2010).

    CAS  PubMed  Google Scholar 

  88. 88

    Ashton-Beaucage, D. et al. The exon junction complex controls the splicing of MAPK and other long intron-containing transcripts in Drosophila. Cell 143, 251–262 (2010).

    CAS  PubMed  Google Scholar 

  89. 89

    Roignant, J. Y. & Treisman, J. E. Exon junction complex subunits are required to splice Drosophila MAP kinase, a large heterochromatic gene. Cell 143, 238–250 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. 90

    Ashton-Beaucage, D. & Therrien, M. The exon junction complex: a splicing factor for long intron containing transcripts? Fly 5, 224–233 (2011).

    CAS  PubMed  Google Scholar 

  91. 91

    Hayashi, R., Handler, D., Ish-Horowicz, D. & Brennecke, J. The exon junction complex is required for definition and excision of neighboring introns in Drosophila. Genes Dev. 28, 1772–1785 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. 92

    Malone, C. D. et al. The exon junction complex controls transposable element activity by ensuring faithful splicing of the piwi transcript. Genes Dev. 28, 1786–1799 (2014). References 91 and 92 document studies in D. melanogaster showing that depositing EJC proteins at piwi transcripts can enhance the splicing of neighbouring weak introns.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. 93

    Haremaki, T. & Weinstein, D. C. Eif4a3 is required for accurate splicing of the Xenopus laevis ryanodine receptor pre-mRNA. Dev. Biol. 372, 103–110 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94

    Michelle, L. et al. Proteins associated with the exon junction complex also control the alternative splicing of apoptotic regulators. Mol. Cell. Biol. 32, 954–967 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Wang, Z., Murigneux, V. & Le Hir, H. Transcriptome-wide modulation of splicing by the exon junction complex. Genome Biol. 15, 551 (2014). A genome-wide study showing that fully-assembled EJCs can affect a large number of splicing events, and that EJC effects are linked to Pol II elongation rates.

    PubMed  PubMed Central  Google Scholar 

  96. 96

    Crabb, T. L., Lam, B. J. & Hertel, K. J. Retention of spliceosomal components along ligated exons ensures efficient removal of multiple introns. RNA 16, 1786–1796 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97

    Kornblihtt, A. R. et al. Alternative splicing: a pivotal step between eukaryotic transcription and translation. Nat. Rev. Mol. Cell Biol. 14, 153–165 (2013).

    CAS  Google Scholar 

  98. 98

    Huang, Y. & Steitz, J. A. Splicing factors SRp20 and 9G8 promote the nucleocytoplasmic export of mRNA. Mol. Cell 7, 899–905 (2001).

    CAS  Google Scholar 

  99. 99

    Gatfield, D. & Izaurralde, E. REF1/Aly and the additional exon junction complex proteins are dispensable for nuclear mRNA export. J. Cell Biol. 159, 579–588 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. 100

    Nott, A., Meislin, S. H. & Moore, M. J. A quantitative analysis of intron effects on mammalian gene expression. RNA 9, 607–617 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. 101

    Kugler, J. M. & Lasko, P. Localization, anchoring and translational control of oskar, gurken, bicoid and nanos mRNA during Drosophila oogenesis. Fly 3, 15–28 (2009).

    CAS  PubMed  Google Scholar 

  102. 102

    Ghosh, S., Marchand, V., Gaspar, I. & Ephrussi, A. Control of RNP motility and localization by a splicing-dependent structure in oskar mRNA. Nat. Struct. Mol. Biol. 19, 441–449 (2012).

    CAS  PubMed  Google Scholar 

  103. 103

    Le Hir, H. & Seraphin, B. EJCs at the heart of translational control. Cell 133, 213–216 (2008).

    CAS  Google Scholar 

  104. 104

    Callis, J., Fromm, M. & Walbot, V. Introns increase gene expression in cultured maize cells. Genes Dev. 1, 1183–1200 (1987).

    CAS  PubMed  Google Scholar 

  105. 105

    Hinnebusch, A. G. The scanning mechanism of eukaryotic translation initiation. Annu. Rev. Biochem. 83, 779–812 (2014).

    CAS  Google Scholar 

  106. 106

    Somers, J., Poyry, T. & Willis, A. E. A perspective on mammalian upstream open reading frame function. Int. J. Biochem. Cell Biol. 45, 1690–1700 (2013).

    CAS  Google Scholar 

  107. 107

    Le Hir, H., Moore, M. J. & Maquat, L. E. Pre-mRNA splicing alters mRNP composition: evidence for stable association of proteins at exon–exon junctions. Genes Dev. 14, 1098–1108 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  108. 108

    Yamashita, A. et al. SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay. Genes Dev. 23, 1091–1105 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  109. 109

    Hug, N. & Caceres, J. F. The RNA helicase DHX34 activates NMD by promoting a transition from the surveillance to the decay-inducing complex. Cell Rep. 8, 1845–1856 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. 110

    Kurosaki, T. et al. A post-translational regulatory switch on UPF1 controls targeted mRNA degradation. Genes Dev. 28, 1900–1916 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. 111

    Isken, O. et al. Upf1 phosphorylation triggers translational repression during nonsense-mediated mRNA decay. Cell 133, 314–327 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. 112

    Okada-Katsuhata, Y. et al. N- and C-terminal Upf1 phosphorylations create binding platforms for SMG-6 and SMG-5:SMG-7 during NMD. Nucleic Acids Res. 40, 1251–1266 (2012).

    CAS  Google Scholar 

  113. 113

    Chan, W. K. et al. An alternative branch of the nonsense-mediated decay pathway. EMBO J. 26, 1820–1830 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. 114

    Chakrabarti, S. et al. Molecular mechanisms for the RNA-dependent ATPase activity of Upf1 and its regulation by Upf2. Mol. Cell 41, 693–703 (2011).

    CAS  Google Scholar 

  115. 115

    Fiorini, F., Boudvillain, M. & Le Hir, H. Tight intramolecular regulation of the human Upf1 helicase by its N- and C-terminal domains. Nucleic Acids Res. 41, 2404–2415 (2013).

    CAS  Google Scholar 

  116. 116

    Franks, T. M., Singh, G. & Lykke-Andersen, J. Upf1 ATPase-dependent mRNP disassembly is required for completion of nonsense- mediated mRNA decay. Cell 143, 938–950 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. 117

    Fiorini, F., Bagchi, D., Le Hir, H. & Croquette, V. Human Upf1 is a highly processive RNA helicase and translocase with RNP remodelling activities. Nat. Commun. 6, 7581 (2015).

    PubMed  PubMed Central  Google Scholar 

  118. 118

    Giorgi, C. et al. The EJC factor eIF4AIII modulates synaptic strength and neuronal protein expression. Cell 130, 179–191 (2007). This study showed that changes in eIF4A3 levels cause changes in several neuronal-specific mRNAs, some of which are regulated by EJC-dependent translational decay.

    CAS  Google Scholar 

  119. 119

    Amrani, N. et al. A faux 3′-UTR promotes aberrant termination and triggers nonsense-mediated mRNA decay. Nature 432, 112–118 (2004).

    CAS  Google Scholar 

  120. 120

    Brogna, S. & Wen, J. Nonsense-mediated mRNA decay (NMD) mechanisms. Nat. Struct. Mol. Biol. 16, 107–113 (2009).

    CAS  PubMed  Google Scholar 

  121. 121

    Buhler, M., Steiner, S., Mohn, F., Paillusson, A. & Muhlemann, O. EJC-independent degradation of nonsense immunoglobulin-μ mRNA depends on 3′ UTR length. Nat. Struct. Mol. Biol. 13, 462–464 (2006).

    Google Scholar 

  122. 122

    Kerenyi, Z. et al. Inter-kingdom conservation of mechanism of nonsense-mediated mRNA decay. EMBO J. 27, 1585–1595 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. 123

    Wen, J. & Brogna, S. Splicing-dependent NMD does not require the EJC in Schizosaccharomyces pombe. EMBO J. 29, 1537–1551 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. 124

    Wittkopp, N. et al. Nonsense-mediated mRNA decay effectors are essential for zebrafish embryonic development and survival. Mol. Cell. Biol. 29, 3517–3528 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. 125

    Gatfield, D., Unterholzner, L., Ciccarelli, F. D., Bork, P. & Izaurralde, E. Nonsense-mediated mRNA decay in Drosophila: at the intersection of the yeast and mammalian pathways. EMBO J. 22, 3960–3970 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. 126

    Longman, D., Plasterk, R. H., Johnstone, I. L. & Caceres, J. F. Mechanistic insights and identification of two novel factors in the C. elegans NMD pathway. Genes Dev. 21, 1075–1085 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. 127

    Hachet, O. & Ephrussi, A. Splicing of oskar RNA in the nucleus is coupled to its cytoplasmic localization. Nature 428, 959–963 (2004). This study provided the first evidence that splicing and the EJC are both required for the localization of an mRNA, and implied the potential differential occupancy of EJCs.

    CAS  PubMed  Google Scholar 

  128. 128

    Sauliere, J. et al. The exon junction complex differentially marks spliced junctions. Nat. Struct. Mol. Biol. 17, 1269–1271 (2010).

    CAS  PubMed  Google Scholar 

  129. 129

    Muhlemann, O. Intimate liaison with SR proteins brings exon junction complexes to unexpected places. Nat. Struct. Mol. Biol. 19, 1209–1211 (2012).

    PubMed  Google Scholar 

  130. 130

    Mishler, D. M., Christ, A. B. & Steitz, J. A. Flexibility in the site of exon junction complex deposition revealed by functional group and RNA secondary structure alterations in the splicing substrate. RNA 14, 2657–2670 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. 131

    Huang, Y. & Steitz, J. A. SRprises along a messenger's journey. Mol. Cell 17, 613–615 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. 132

    Zhang, Z. & Krainer, A. R. Involvement of SR proteins in mRNA surveillance. Mol. Cell 16, 597–607 (2004).

    CAS  Google Scholar 

  133. 133

    Sato, H., Hosoda, N. & Maquat, L. E. Efficiency of the pioneer round of translation affects the cellular site of nonsense-mediated mRNA decay. Mol. Cell 29, 255–262 (2008).

    CAS  Google Scholar 

  134. 134

    Michlewski, G., Sanford, J. R. & Caceres, J. F. The splicing factor SF2/ASF regulates translation initiation by enhancing phosphorylation of 4E-BP1. Mol. Cell 30, 179–189 (2008).

    CAS  Google Scholar 

  135. 135

    Gudikote, J. P., Imam, J. S., Garcia, R. F. & Wilkinson, M. F. RNA splicing promotes translation and RNA surveillance. Nat. Struct. Mol. Biol. 12, 801–809 (2005).

    CAS  Google Scholar 

  136. 136

    Viegas, M. H., Gehring, N. H., Breit, S., Hentze, M. W. & Kulozik, A. E. The abundance of RNPS1, a protein component of the exon junction complex, can determine the variability in efficiency of the Nonsense Mediated Decay pathway. Nucleic Acids Res. 35, 4542–4551 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. 137

    Zetoune, A. B. et al. Comparison of nonsense-mediated mRNA decay efficiency in various murine tissues. BMC Genet. 9, 83 (2008).

    PubMed  PubMed Central  Google Scholar 

  138. 138

    Moore, M. J. & Proudfoot, N. J. Pre-mRNA processing reaches back to transcription and ahead to translation. Cell 136, 688–700 (2009).

    CAS  Google Scholar 

  139. 139

    Baltz, A. G. et al. The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. Mol. Cell 46, 674–690 (2012).

    CAS  Google Scholar 

  140. 140

    Castello, A. et al. Insights into RNA biology from an atlas of mammalian mRNA-binding proteins. Cell 149, 1393–1406 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. 141

    Silver, D. L. et al. The exon junction complex component Magoh controls brain size by regulating neural stem cell division. Nat. Neurosci. 13, 551–558 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. 142

    Boswell, R. E., Prout, M. E. & Steichen, J. C. Mutations in a newly identified Drosophila melanogaster gene, mago nashi, disrupt germ cell formation and result in the formation of mirror-image symmetrical double abdomen embryos. Development 113, 373–384 (1991).

    CAS  PubMed  Google Scholar 

  143. 143

    Parma, D. H., Bennett, P. E. Jr & Boswell, R. E. Mago Nashi and Tsunagi/Y14, respectively, regulate Drosophila germline stem cell differentiation and oocyte specification. Dev. Biol. 308, 507–519 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. 144

    Lewandowski, J. P., Sheehan, K. B., Bennett, P. E. Jr & Boswell, R. E. Mago Nashi, Tsunagi/Y14, and Ranshi form a complex that influences oocyte differentiation in Drosophila melanogaster. Dev. Biol. 339, 307–319 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. 145

    van der Weele, C. M., Tsai, C. W. & Wolniak, S. M. Mago nashi is essential for spermatogenesis in Marsilea. Mol. Biol. Cell 18, 3711–3722 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  146. 146

    Boothby, T. C. & Wolniak, S. M. Masked mRNA is stored with aggregated nuclear speckles and its asymmetric redistribution requires a homolog of Mago nashi. BMC Cell Biol. 12, 45 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. 147

    Kawano, T., Kataoka, N., Dreyfuss, G. & Sakamoto, H. Ce-Y14 and MAG-1, components of the exon–exon junction complex, are required for embryogenesis and germline sexual switching in Caenorhabditis elegans. Mech. Dev. 121, 27–35 (2004).

    CAS  PubMed  Google Scholar 

  148. 148

    Inaki, M. et al. Genetic analyses using a mouse cell cycle mutant identifies magoh as a novel gene involved in Cdk regulation. Genes Cells 16, 166–178 (2011).

    CAS  PubMed  Google Scholar 

  149. 149

    Mao, H. et al. Rbm8a haploinsufficiency disrupts embryonic cortical development resulting in microcephaly. J. Neurosci. 35, 7003–7018 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. 150

    Silver, D. L., Leeds, K. E., Hwang, H. W., Miller, E. E. & Pavan, W. J. The EJC component Magoh regulates proliferation and expansion of neural crest-derived melanocytes. Dev. Biol. 375, 172–181 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. 151

    Haremaki, T., Sridharan, J., Dvora, S. & Weinstein, D. C. Regulation of vertebrate embryogenesis by the exon junction complex core component Eif4a3. Dev. Dyn. 239, 1977–1987 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. 152

    Barker-Haliski, M. L., Pastuzyn, E. D. & Keefe, K. A. Expression of the core exon-junction complex factor eukaryotic initiation factor 4A3 is increased during spatial exploration and striatally-mediated learning. Neuroscience 226, 51–61 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. 153

    Alachkar, A. et al. An EJC factor RBM8a regulates anxiety behaviors. Curr. Mol. Med. 13, 887–899 (2013).

    CAS  PubMed  Google Scholar 

  154. 154

    Nguyen, L. S. et al. Contribution of copy number variants involving nonsense-mediated mRNA decay pathway genes to neuro-developmental disorders. Hum. Mol. Genet. 22, 1816–1825 (2013).

    CAS  Google Scholar 

  155. 155

    Albers, C. A. et al. Compound inheritance of a low-frequency regulatory SNP and a rare null mutation in exon-junction complex subunit RBM8A causes TAR syndrome. Nat. Genet. 44, 435–439 (2012). The first study to link mutations in Y14 to a human disease. In this case, Y14 expression is reduced in platelets, causing TAR syndrome.

    CAS  PubMed  PubMed Central  Google Scholar 

  156. 156

    Favaro, F. P. et al. A noncoding expansion in EIF4A3 causes Richieri-Costa-Pereira syndrome, a craniofacial disorder associated with limb defects. Am. J. Hum. Genet. 94, 120–128 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  157. 157

    Chan, C. C. et al. eIF4A3 is a novel component of the exon junction complex. RNA 10, 200–209 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. 158

    Ferraiuolo, M. A. et al. A nuclear translation-like factor eIF4AIII is recruited to the mRNA during splicing and functions in nonsense-mediated decay. Proc. Natl Acad. Sci. USA 101, 4118–4123 (2004).

    CAS  PubMed  Google Scholar 

  159. 159

    Palacios, I. M., Gatfield, D., St Johnston, D. & Izaurralde, E. An eIF4AIII-containing complex required for mRNA localization and nonsense-mediated mRNA decay. Nature 427, 753–757 (2004).

    CAS  PubMed  Google Scholar 

  160. 160

    Alexandrov, A., Colognori, D. & Steitz, J. A. Human eIF4AIII interacts with an eIF4G-like partner, NOM1, revealing an evolutionarily conserved function outside the exon junction complex. Genes Dev. 25, 1078–1090 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. 161

    Budiman, M. E. et al. Eukaryotic initiation factor 4a3 is a selenium-regulated RNA-binding protein that selectively inhibits selenocysteine incorporation. Mol. Cell 35, 479–489 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. 162

    Zhao, X. F., Nowak, N. J., Shows, T. B. & Aplan, P. D. MAGOH interacts with a novel RNA-binding protein. Genomics 63, 145–148 (2000).

    CAS  PubMed  Google Scholar 

  163. 163

    Hachet, O. & Ephrussi, A. Drosophila Y14 shuttles to the posterior of the oocyte and is required for oskar mRNA transport. Curr. Biol. 11, 1666–1674 (2001).

    CAS  PubMed  Google Scholar 

  164. 164

    Mohr, S. E., Dillon, S. T. & Boswell, R. E. The RNA-binding protein Tsunagi interacts with Mago Nashi to establish polarity and localize oskar mRNA during Drosophila oogenesis. Genes Dev. 15, 2886–2899 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  165. 165

    Kataoka, N., Diem, M. D., Kim, V. N., Yong, J. & Dreyfuss, G. Magoh, a human homolog of Drosophila mago nashi protein, is a component of the splicing-dependent exon–exon junction complex. EMBO J. 20, 6424–6433 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. 166

    Le Hir, H., Gatfield, D., Braun, I. C., Forler, D. & Izaurralde, E. The protein Mago provides a link between splicing and mRNA localization. EMBO Rep. 2, 1119–1124 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  167. 167

    Baguet, A. et al. The exon-junction-complex-component metastatic lymph node 51 functions in stress-granule assembly. J. Cell Sci. 120, 2774–2784 (2007).

    CAS  PubMed  Google Scholar 

  168. 168

    Mayeda, A. et al. Purification and characterization of human RNPS1: a general activator of pre-mRNA splicing. EMBO J. 18, 4560–4570 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. 169

    Singh, G., Jakob, S., Kleedehn, M. G. & Lykke-Andersen, J. Communication with the exon-junction complex and activation of nonsense-mediated decay by human Upf proteins occur in the cytoplasm. Mol. Cell 27, 780–792 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. 170

    Sahara, S. et al. Acinus is a caspase-3-activated protein required for apoptotic chromatin condensation. Nature 401, 168–173 (1999).

    CAS  PubMed  Google Scholar 

  171. 171

    Li, C., Lin, R. I., Lai, M. C., Ouyang, P. & Tarn, W. Y. Nuclear Pnn/DRS protein binds to spliced mRNPs and participates in mRNA processing and export via interaction with RNPS1. Mol. Cell. Biol. 23, 7363–7376 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. 172

    Rodrigues, J. P. et al. REF proteins mediate the export of spliced and unspliced mRNAs from the nucleus. Proc. Natl Acad. Sci. USA 98, 1030–1035 (2001).

    CAS  PubMed  Google Scholar 

  173. 173

    Zhou, Z. et al. The protein Aly links pre-messenger-RNA splicing to nuclear export in metazoans. Nature 407, 401–405 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. 174

    Gatfield, D. et al. The DExH/D box protein HEL/UAP56 is essential for mRNA nuclear export in Drosophila. Curr. Biol. 11, 1716–1721 (2001).

    CAS  PubMed  Google Scholar 

  175. 175

    Braun, I. C., Herold, A., Rode, M., Conti, E. & Izaurralde, E. Overexpression of TAP/p15 heterodimers bypasses nuclear retention and stimulates nuclear mRNA export. J. Biol. Chem. 276, 20536–20543 (2001).

    CAS  PubMed  Google Scholar 

  176. 176

    Fribourg, S., Braun, I. C., Izaurralde, E. & Conti, E. Structural basis for the recognition of a nucleoporin FG repeat by the NTF2-like domain of the TAP/p15 mRNA nuclear export factor. Mol. Cell 8, 645–656 (2001).

    CAS  Google Scholar 

  177. 177

    Chan, W. K. et al. A UPF3-mediated regulatory switch that maintains RNA surveillance. Nat. Struct. Mol. Biol. 16, 747–753 (2009).

    CAS  PubMed  Google Scholar 

  178. 178

    Kadlec, J., Izaurralde, E. & Cusack, S. The structural basis for the interaction between nonsense-mediated mRNA decay factors UPF2 and UPF3. Nat. Struct. Mol. Biol. 11, 330–337 (2004).

    CAS  PubMed  Google Scholar 

  179. 179

    Kadlec, J., Guilligay, D., Ravelli, R. B. & Cusack, S. Crystal structure of the UPF2-interacting domain of nonsense-mediated mRNA decay factor UPF1. RNA 12, 1817–1824 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  180. 180

    Unterholzner, L. & Izaurralde, E. SMG7 acts as a molecular link between mRNA surveillance and mRNA decay. Mol. Cell 16, 587–596 (2004).

    CAS  Google Scholar 

Download references

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.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Hervé Le Hir.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Related links

Related links

DATABASES

Protein Data Bank

2XB2

4C9B

1RK8

FURTHER INFORMATION

The Cancer Genome Atlas

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.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Further reading