Reactome | Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)

Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)

Stable Identifier

R-HSA-975957

Type

Pathway

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

Locations in the PathwayBrowser

Expand all

General

SBML | | PDF

SVG | | PPTX | SBGN

Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)

Click the image above or here to open this pathway in the Pathway Browser

During normal translation termination eRF3 associates with the ribosome and then interacts with PABP bound to the polyadenylate tail of the mRNA to release the ribosome and allow a new round of translation to commence. Nonsense-mediated decay (NMD) is triggered if eRF3 at the ribosome interacts with UPF1, which may compete with PABP (reviewed in Isken and Maquat 2007, Chang et al. 2007, Behm-Ansmant et al. 2007, Rebbapragada and Lykke-Andersen 2009, Bhuvanagiri et al. 2010, Nicholson et al. 2010, Durand and Lykke-Andersen 2011). An exon junction located 50-55 nt downstream of a termination codon is observed to enhance NMD.
Exon-junction complexes (EJCs) are deposited on the mRNA during splicing in the nucleus, remain on mRNAs after transport to the cytosol, and are dislodged by the ribosome as it progresses along the mRNA during the pioneer round of translation (Gehring et al. 2009). EJCs contain the core factors eIF4A-III, Magoh-Y14, and CASC3 as well as the peripheral factors RNPS1, UPF2, and UPF3. UPF2 and UPF3 recruit UPF1 to eRF3 at the terminating ribosome. Thus an EJC downstream of a termination codon will not have been dislodged during translation and will recruit UPF1, triggering NMD.
UPF1 is believed to form a complex containing SMG1, SMG8, and SMG9. In the key regulatory step of NMD SMG1 phosphorylates UPF1. The phosphorylated UPF1 then recruits either SMG6 or SMG5 and SMG7. SMG6 is itself an endoribonuclease that cleaves the mRNA. SMG5 and SMG7 do not have endoribonuclease activty, but are thought to recruit ribonucleases. Nonsense-mediated decay has been observed to involve deadenlyation, decapping, and both 5' to 3' and 3' to 5' exonuclease activities, but the exact degradative pathways taken by a given mRNA are not yet known.
UPF1 also plays roles in Staufen-mediated decay, histone mRNA decay, telomere maintenance, genome integrity, and may play a role in normal termination of translation.

Literature References

PubMed ID	Title	Journal	Year
19859661	Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors Yepiskoposyan, H, Kleinschmidt, N, Zamudio Orozco, R, Metze, S, Muhlemann, O, Nicholson, P	Cell Mol Life Sci	2010
17531985	mRNA quality control: an ancient machinery recognizes and degrades mRNAs with nonsense codons Saulière, J, Wittkopp, N, Behm-Ansmant, I, Izaurralde, E, Rehwinkel, J, Kashima, I	FEBS Lett	2007
21496649	SnapShot: Nonsense-Mediated mRNA Decay Durand, S, Lykke-Andersen, J	Cell	2011
19410547	Disassembly of exon junction complexes by PYM Gehring, NH, Lamprinaki, S, Kulozik, AE, Hentze, MW	Cell	2009
20795950	NMD: RNA biology meets human genetic medicine Bhuvanagiri, M, Kulozik, AE, Hentze, MW, Schlitter, AM	Biochem J	2010
17352659	The nonsense-mediated decay RNA surveillance pathway Wilkinson, MF, Imam, JS, Chang, YF	Annu Rev Biochem	2007
19359157	Execution of nonsense-mediated mRNA decay: what defines a substrate? Rebbapragada, I, Lykke-Andersen, J	Curr Opin Cell Biol	2009
17671086	Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function Isken, O, Maquat, LE	Genes Dev	2007