This Title All WIREs
How to cite this WIREs title:
Impact Factor: 9.957

The exon junction complex: a lifelong guardian of mRNA fate

Full article on Wiley Online Library:   HTML PDF

Can't access this content? Tell your librarian.

During messenger RNA (mRNA) biogenesis and processing in the nucleus, many proteins are imprinted on mRNAs assembling them into messenger ribonucleoproteins (mRNPs). Some of these proteins remain stably bound within mRNPs and have a long‐lasting impact on their fate. One of the best‐studied examples is the exon junction complex (EJC), a multiprotein complex deposited primarily 24 nucleotides upstream of exon–exon junctions as a consequence of pre‐mRNA splicing. The EJC maintains a stable, sequence‐independent, hold on the mRNA until its removal during translation in the cytoplasm. Acting as a molecular shepherd, the EJC travels with mRNA across the cellular landscape coupling pre‐mRNA splicing to downstream, posttranscriptional processes such as mRNA export, mRNA localization, translation, and nonsense‐mediated mRNA decay (NMD). In this review, we discuss our current understanding of the EJC’s functions during these processes, and expound its newly discovered functions (e.g., pre‐mRNA splicing). Another focal point is the recently unveiled in vivo EJC interactome, which has shed new light on the EJC's location on the spliced RNAs and its intimate relationship with other mRNP components. We summarize new strides being made in connecting the EJC’s molecular function with phenotypes, informed by studies of human disorders and model organisms. The progress toward understanding EJC functions has revealed, in its wake, even more questions, which are discussed throughout. WIREs RNA 2017, 8:e1411. doi: 10.1002/wrna.1411 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Processing > Splicing Regulation/Alternative Splicing RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
The exon junction complex (EJC) cycle. (i) The EJC subunits are recruited co‐transcriptionally to the activated spliceosome. The recruitment of eIF4AIII occurs via interaction with CWC22. (ii) Upon exon ligation and release, the EJC is stably bound to messenger RNA (mRNA) 24 nt upstream of exon–exon junctions. In addition to the core, many peripheral factors are deposited in a splicing‐dependent manner (indicated by a gray oval around EJC core). Specific examples of nuclear peripheral factors are indicated: TREX, ASAP, and Upf3b. (iii) Some peripheral factors are removed prior to export, while others remain bound and travel with the EJC into the cytoplasm. (iv) MLN51 (purple) is present with the complex in the cytoplasm after it joins the EJC postsplicing, either in the nucleus or in the cytoplasm. (v) 40S ribosome subunit‐associated protein, PYM (red), allows for translation‐dependent disassembly of the EJC during the first (pioneer) round of translation. (vi) Following disassembly, the Y14:Magoh heterodimer is reimported to the nucleus via Imp13. The mechanisms of eIF4AIII and MLN51 nuclear import are unknown. Recycled subunits can reenter the EJC cycle. Thick gray lines, exons; thin gray line, intron; thick black lines, DNA; black circle, mRNA cap.
[ Normal View | Magnified View ]
Postsplicing functions of exon junction complex (EJC) during gene expression. (a) Messenger ribonucleoprotein (mRNP) packaging: Interactions between multiple EJC cores deposited on neighboring exons, and between cEJCs and ncEJCs, drive a linear mRNP (top) into a three‐dimensionally packaged mRNP (bottom). Protein–protein interactions are illustrated by thick dashed lines. (b) mRNP export: Two modes of EJC‐dependent mRNA export: Left: On mRNAs that contain introns in their 5′UTRs the EJC and mRNA cap recruit the TREX complex (THO complex, Aly/REF and UAP56), which in turn recruits export receptor, TAP/p15. Right: On mRNAs lacking 5'‐UTR introns, the EJC may partner with ALREX element‐bound proteins, which in turn recruit TAP/p15 (right). RNA region corresponding to signal sequence coding region (SSCR) that also contains ALREX element is shown in blue. Postsplicing functions of EJC during gene expression.(c) Translation: Two mechanisms for EJC‐dependent translation enhancement: (i) MLN51 directly interacts with eIF3 components within the 43S preinitiation complex (PIC) to recruit it to the eIF4G bound close to the 5′ methyl‐guanosine cap. (ii) In response to stimuli, mTORC1 phosphorylates S6K1 causing its release from eIF3 and incorporation of activated S6K1 into mRNPs via SKAR. S6K1 may aid in translation initiation by phosphorylating downstream effectors within mRNPs such as eIF4B. Black arrows denote phosphorylation events whereas light blue arrows represent protein recruitment. (d) Nonsense‐mediated mRNA decay: An EJC >50 nt downstream (dsEJC) of a termination codon activates nonsense‐mediated mRNA decay (NMD) by recruiting Upf factors via multiple interactions. Following translation termination, Upf1, Smg1, and eRFs (1 and 3) along with other factors (indicated by a gray cloud) assemble into a SURF complex. Downstream EJC can enhance Upf1 activation by positioning Upf2 and/or Upf3 in the close proximity of the SURF complex. Arrows show how EJC can promote Upf1–Upf2–Upf3‐dependent, or Upf2‐independent, or Upf3‐independent NMD complexes.
[ Normal View | Magnified View ]
Two modes of exon junction complex (EJC) function during pre‐messenger RNA (mRNA) splicing. (a) EJC modulates RNA polymerase II (Pol II) elongation rate to control alternative splicing. The presence of EJC (left) slows down RNA Pol II elongation (shown by the inhibitory arrow) to introduce a delay in transcription of downstream strong splice site. This provides more time for splicing to occur at available weak splice sites (exons connected by solid blue lines). In the absence of EJC (right), faster RNA Pol II elongation rate reveals the stronger downstream splice sites more rapidly, leading to exon skipping due to the use of downstream splice site (exons connected by solid red lines) and omission of weaker splice sites (shown by dotted blue lines). Instead of exon skipping, such a scenario can also lead to retention of first intron shown in the schematic if 5'‐splice site of intron 2 is used (not shown). (b) EJC acts as a splicing cofactor to control pre‐mRNA splicing. EJC recruits/stabilizes SR proteins (e.g., SRSF1) or SR‐like proteins (e.g., RNPS1, Acinus) to enhance splice‐site recognition and spliceosome assembly.
[ Normal View | Magnified View ]
Two possible models for origin of noncanonical exon junction complexes (ncEJCs). (a) Both cEJC and ncEJC consist of EJC core factors, and could be stabilized by nearby EJC‐interacting RNA‐binding proteins (RBPs; e.g., SR proteins; orange shape). The site on RNA directly in contact with eIF4AIII is shown in red, whereas sites of EJC‐interacting RBPs are in purple. (b) Unlike canonical EJCs, which consist of the core factors, the ncEJCs are binding sites for EJC‐binding proteins, such as SR proteins. Interactions between cEJCs and ncEJCs may be bridged by other EJC‐interacting proteins (gray oval).
[ Normal View | Magnified View ]
Competing mutually exclusive protein–protein interactions at the exon junction complex (EJC) core. (a) eIF4AIII in its open conformation interacts with MIF4G domain of either CWC22 or Nom1. (b) Two surfaces of EJC core engage in competing interactions. Similar EJC‐binding motifs (EBMs) on Upf3a, Upf3b, and Smg6 recognize a composite surface of the assembled EJC core. MLN51 and Aly/REF possess similar sequence motifs that may compete to bind a conserved surface on eIF4AIII. Sites of competing interactions on the EJC core are indicated in lighter shade. (c) The Y14:Magoh heterodimer participates in at least three mutually exclusive interactions: with eIF4AIII, in the context of EJC assembly; with PYM, during and after EJC disassembly; and with Imp13, for reimport into the nucleus.
[ Normal View | Magnified View ]

Browse by Topic

RNA Processing > Splicing Regulation/Alternative Splicing
RNA Turnover and Surveillance > Turnover/Surveillance Mechanisms
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications

Access to this WIREs title is by subscription only.

Recommend to Your
Librarian Now!

The latest WIREs articles in your inbox

Sign Up for Article Alerts