Nonsense-Mediated Decay (NMD) (Homo sapiens)

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1, 14, 16, 19, 21...2, 4, 5, 8, 10...12, 26, 27, 30, 31, 46...2, 51, 572, 5, 7, 8, 10...13, 18, 22, 25, 35...3, 6, 9, 11, 15...cytosolNonsense-mediated Decay Independent of the Exon Junction ComplexNonsense-mediated Decay Enhanced by the Exon Junction ComplexRPL19 ATPRPS18 RPS4X RPL38 RPS25 RPLP0 RPL26L1 RPS3 RPS2 RPL6 RPL17 RPL3L RPL37A RPS15 EIF4G1 RPS29 RPL7 RPS11 RPL23A RPL7 RPL32 RPS12 RPL35A RPL37A RPS10 RPS16 ETF1 RPS28 RPS19 RPL31 RPS11 RPL34 RPL26L1 RPS15A RPL35A RPL15 RPL30 RPS29 RPSA PABPC1 GDP RPLP0 RPS13 RPS15A RPL8 RPL3 GSPT2 SMG5 Translated mRNAComplex withPrematureTermination CodonPreceding ExonJunctionRPL11 RBM8A RPL8 ETF1 GSPT2 PPP2R1A RPS2 RPS7 EIF4G1 RPL41 28S rRNA RPS7 RPS5 RPS16 RPS26 RPL18A RPL11 18S rRNA RPL39 PABPC1 PABPC1 RPS13 RPL38 RPS20 SMG7 RPS8 RPS25 5.8S rRNA RPLP1 RPS20 RPS12 RPL17 RPL27 RPS28 RPL21 RPS15A RPL9 RPL13A RPL14 RPL10A RPS20 RPS21 RPS2 RPLP1 RPL28 RPS29 SMG8 RPS12 RPS12 RPL39 RPS3 RPS21 RPL6 RPS4Y1 RPS5 RPS27 RPS2 GSPT2 RPL27A RPL3L RPL37A 18S rRNA RPL12 RPL19 PPP2CA MAGOH RPS3A RPS10 RPS7 RPL7A RPS19 RPL18 RPS24 RPS4X SMG6 NCBP2 RPL23A RPL3L Translated mRNAComplex withPrematureTermination CodonNot Preceding ExonJunctionRPL18A GSPT2 18S rRNA RPL40 RPL3 RPL41 RPL5 5.8S rRNA RPL14 MAGOH ETF1 RPL13A RPL27A RPL7 RPL13A RPL15 5S rRNA RPS27 RPS11 NCBP1 RPL27 RPS27 NCBP2 RPS27A(77-156) RPL32 RPL23A RPS10 GDP RPL18A RPL24 RPS12 RPL18 RPL10 UPF2 RPL39 RPL36A RPS10 RPS4Y1 18S rRNA EIF4G1 ADPRPL7A RPL13 RPL32 RPS15A RPL19 RPS3 5S rRNA RPL23 RPL13 RPL4 RPL14 UPF3A RPS17 RPS13 RPL11 RPL19 RPLP1 FAU EIF4A3 RPL15 RPS4X SMG1:SMG8:SMG9ComplexRPL26L1 28S rRNA RPL6 RPS24 RPL28 EIF4G1 RPL12 RPL26 RPL8 5.8S rRNA RPL34 RPL10A EIF4G1RPL17 RPS23 RPS16 RPS16 RPL27 RPS10 RPLP2 RPS2 CASC3 RPL30 SMG1:UPF1:EJC:Translated mRNPRPSA 18S rRNA RPS18 RPLP0 RPS3A RPS14 RPS3 RPS17 RPL26L1 RPL34 RPL5 RPL7A RPL26 SMG1 RPS24 RPL22 RPL27A RPL4 RPSA RPL36 FAU RPL31 RPL3 p-4S-UPF1 RPS4Y1 RPL14 RPS5 RPL29 RPS13 RPL23A EIF4A3 RPL12 RPL7A RPL28 RPL35 RPL37A RPL26L1 RPL30 RPL10 RPS6 PPP2R2A RPL23A RPL4 RPS11 RPL21 RPS25 RPL10 PABPC1 RPL22 RPL15 RPL26L1 RPL23 RPL38 PABPC1 RPS6 RPL27 RPS9 RPL3L RPS3 RPS8 RPL24 RPL18 RPS26 UPF3AS-2 NCBP1 UPF1:eRF3 Complex onTranslated mRNARPS12 RPL35A RPS4X RPS28 RPS16 RPL23 RPS18 RPL17 RPL27A RPL31 RPL24 RPL8 FAU RPS19 RPL27 RPL29 RPL39 RPL36 RPL5 RPS27A(77-156) NCBP1 RPL9 PPP2R2A RBM8A RPSA RPL37 RPS8 GSPT2 RPS19 RPL8 5S rRNA FAU RPL35A RPL24 UPF1 RPS17 RPS26 RPL23 RPS27A(77-156) RPL7A RPL13 RPS9 RPL32 NCBP2 28S rRNA RPL37 RBM8A 5S rRNA RPL13A RPL24 RPL34 UPF1RPS25 RPLP1 RPS18 RPS9 RPL36A RPL32 GSPT2 RPL3L PABPC1 SMG9 RPS15A RPL37 RPL9 RPS15 RPS15A RPS11 PP2A(Aalpha:B55alpha:Calpha)RPL31 RPL41 NCBP2 RPL32 NCBP2 RPS15 UPF3A RPL22 RPL36 RPL3 p-4S-UPF1 RPS23 SMG8 RPS7 RPL41 RPS8 RPS15 RPL5 RPS9 RPS26 RPL11 RPL11 RPL29 RPLP2 RNPS1 RPS5 SMG5 RPL9 SMG7RPL5 RPL23A RPL3 UPF2 RPL37 RPS7 RPL12 RPS14 RPL35 RPS15 RPL4 RPS28 PPP2CA RPL30 NCBP1 RPS6 PhosphorylatedUPF1:SMG5:SMG7:SMG6:PP2A:Translated mRNPRPS23 RPS27A(77-156) RPL12 SMG7 NCBP2 GDP CASC3 RPS4Y1 RPLP0 EIF4A3 RPL6 RPL6 RPS27A(77-156) RPS27A(77-156) FAU RPL41 RPS25 RPL34 RPL28 5S rRNA RBM8A RPS26 RPL7A RPL36A UPF3A EIF4G1 RPL35 5.8S rRNA p-4S-UPF1 RPL22 28S rRNA RPL6 RPS21 RPL35 RPL12 RPL13 RPL27A MAGOH RPL39 RPL18A RPL9 RPL23 RPL19 RPL7 NCBP1 UPF2 RPS10 RPL8 28S rRNA RPS9 RPL7 RPS8 RPS23 SMG1:PhosphorylatedUPF1:EJC:TranslatedmRNPRPLP0 RPL10A FAU RPS6 RPS2 5.8S rRNA RPL30 RPS11 RNPS1 RPL29 RPL36A RPL21 EIF4A3 RPL40 UPF3B RPS4Y1 UPF3B RPL27 SMG6RPL28 RPL23 mRNA Cleaved by SMG6RPL21 RPL17 SMG1 5.8S rRNA RPL18 RPL28 PABPC1RPL31 PPP2R1A NCBP1 RPS18 RPS16 RPL13A RPS6 RPL18A RPL36A RPL36 RPS3A RPLP1 RPS5 RPS27 UPF1 RPL18 RPL9 UPF2 RPS28 RPS21 RPS13 RPL38 RPL4 RPL37 RPL21 5S rRNA RPS14 ETF1 SMG1 RPL26 18S rRNA RPL37 SMG9 RPL29 RPS3A RPL40 GDP RPS24 RPS23 RPL35A RPS29 RPL37A NCBP1 RPS7 NCBP2 RPL22 RPL10A RPL10 RPL34 PPP2R1A RPL38 SMG6 PABPC1 RPS19 RPS14 RPS18 RPL26 NCBP2 RPLP2 GDP RPS21 RPLP2 RPL19 RPL14 RPL39 RPS26 RPS17 RPL15 RPL40 RPL11 EIF4G1 GDP RPS19 SMG5RPL35 RNPS1 RPL36 RPS3A SMG9 RPL13A RPL21 PPP2R2A RPS4X RPS3 RPL26 RPL17 RPS8 RPL30 RPS27 RPL35 RPL27A RPS4Y1 RPS29 Cap Binding Complex(CBC)RPL18A UPF3A UPF3B RPS20 RPL35A RPS24 RPL29 NCBP1 RPL4 RPL13 MAGOH RPS5 RPS25 CASC3 RPL41 ETF1 RPS28 RPS21 RPL36A RPS20 RPLP2 RPL36 RPL26 RPS29 RPL10 RPL13 ETF1 RPSA UPF3B RPLP1 RPL37A RPS20 EIF4G1 RPL10 RPL24 RNPS1 RPL10A RPL38 RPL40 RPS3A RPL3 p-4S-UPF1SMG8 RPS15 RPL15 RPS27 RPLP2 RPL14 RPS17 RPS24 RPLP0 PPP2CA RPS14 RPL22 28S rRNA RPL10A CASC3 RPS23 RPS14 RPS13 RPL40 RPL18 RPS4X RPS9 RPL7 RPL31 RPSA RPS6 RPL3L RPL5 RPS17 267, 47358


Description

The Nonsense-Mediated Decay (NMD) pathway activates the destruction of mRNAs containing premature termination codons (PTCs) (reviewed in Isken and Maquat 2007, Chang et al. 2007, Behm-Ansmant et al. 2007, Neu-Yilik and Kulozik 2008, Rebbapragada and Lykke-Andersen 2009, Bhuvanagiri et al. 2010, Nicholson et al. 2010, Durand and Lykke-Andersen 2011). In mammalian cells a termination codon can be recognized as premature if it precedes an exon-exon junction by at least 50-55 nucleotides or if it is followed by an abnormal 3' untranslated region (UTR). While length of the UTR may play a part, the qualifications for being "abnormal" have not been fully elucidated. Also, some termination codons preceding exon junctions are not degraded by NMD so the criteria for triggering NMD are not yet fully known (reviewed in Rebbapragada and Lykke-Andersen 2009). While about 30% of disease-associated mutations in humans activate NMD, about 10% of normal human transcripts are also degraded by NMD (reviewed in Stalder and Muhlemann 2008, Neu-Yilik and Kulozik 2008, Bhuvanagiri et al. 2010, Nicholson et al. 2010). Thus NMD is a normal physiological process controlling mRNA stability in unmutated cells.
Exon junction complexes (EJCs) are deposited on an mRNA during splicing in the nucleus and are displaced by ribosomes during the first round of translation. When a ribosome terminates translation the A site encounters the termination codon and the eRF1 factor enters the empty A site and recruits eRF3. Normally, eRF1 cleaves the translated polypeptide from the tRNA in the P site and eRF3 interacts with Polyadenylate-binding protein (PABP) bound to the polyadenylated tail of the mRNA.
During activation of NMD eRF3 interacts with UPF1 which is contained in a complex with SMG1, SMG8, and SMG9. NMD can arbitrarily be divided into EJC-enhanced and EJC-independent pathways. In EJC-enhanced NMD, an exon junction is located downstream of the PTC and the EJC remains on the mRNA after termination of the pioneer round of translation. The core EJC is associated with UPF2 and UPF3, which interact with UPF1 and stimulate NMD. Once bound near the PTC, UPF1 is phosphorylated by SMG1. The phosphorylation is the rate-limiting step in NMD and causes UPF1 to recruit either SMG6, which is an endoribonuclease, or SMG5 and SMG7, which recruit ribonucleases. SMG6 and SMG5:SMG7 recruit phosphatase PP2A to dephosphorylate UPF1 and allow further rounds of degradation. How EJC-independent NMD is activated remains enigmatic but may involve competition between PABP and UPF1 for eRF3. Source:Reactome.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114999view16:53, 25 January 2021ReactomeTeamReactome version 75
113443view11:52, 2 November 2020ReactomeTeamReactome version 74
112643view16:02, 9 October 2020ReactomeTeamReactome version 73
101558view11:43, 1 November 2018ReactomeTeamreactome version 66
101094view21:25, 31 October 2018ReactomeTeamreactome version 65
100623view20:00, 31 October 2018ReactomeTeamreactome version 64
100174view16:44, 31 October 2018ReactomeTeamreactome version 63
99724view15:12, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99298view12:46, 31 October 2018ReactomeTeamreactome version 62
93761view13:34, 16 August 2017ReactomeTeamreactome version 61
93285view11:19, 9 August 2017ReactomeTeamreactome version 61
88067view14:29, 25 July 2016RyanmillerOntology Term : 'regulatory pathway' added !
86369view09:16, 11 July 2016ReactomeTeamreactome version 56
83339view10:50, 18 November 2015ReactomeTeamVersion54
81759view10:00, 26 August 2015ReactomeTeamVersion53
76924view08:19, 17 July 2014ReactomeTeamFixed remaining interactions
76629view12:00, 16 July 2014ReactomeTeamFixed remaining interactions
75960view10:01, 11 June 2014ReactomeTeamRe-fixing comment source
75662view10:56, 10 June 2014ReactomeTeamReactome 48 Update
75017view13:53, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74661view08:43, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
18S rRNA ProteinX03205 (EMBL)
28S rRNA ProteinM11167 (EMBL)
5.8S rRNA ProteinJ01866 (EMBL)
5S rRNA ProteinV00589 (EMBL)
ADPMetaboliteCHEBI:16761 (ChEBI)
ATPMetaboliteCHEBI:15422 (ChEBI)
CASC3 ProteinO15234 (Uniprot-TrEMBL)
Cap Binding Complex (CBC)ComplexR-HSA-162460 (Reactome)
EIF4A3 ProteinP38919 (Uniprot-TrEMBL)
EIF4G1 ProteinQ04637 (Uniprot-TrEMBL)
EIF4G1ProteinQ04637 (Uniprot-TrEMBL)
ETF1 ProteinP62495 (Uniprot-TrEMBL)
FAU ProteinP62861 (Uniprot-TrEMBL)
GDP MetaboliteCHEBI:17552 (ChEBI)
GSPT2 ProteinQ8IYD1 (Uniprot-TrEMBL)
MAGOH ProteinP61326 (Uniprot-TrEMBL)
NCBP1 ProteinQ09161 (Uniprot-TrEMBL)
NCBP2 ProteinP52298 (Uniprot-TrEMBL)
PABPC1 ProteinP11940 (Uniprot-TrEMBL)
PABPC1ProteinP11940 (Uniprot-TrEMBL)
PP2A (Aalpha:B55alpha:Calpha)ComplexR-HSA-377182 (Reactome)
PPP2CA ProteinP67775 (Uniprot-TrEMBL)
PPP2R1A ProteinP30153 (Uniprot-TrEMBL)
PPP2R2A ProteinP63151 (Uniprot-TrEMBL)
Phosphorylated UPF1:SMG5:SMG7:SMG6:PP2A:Translated mRNPComplexR-HSA-927854 (Reactome)
RBM8A ProteinQ9Y5S9 (Uniprot-TrEMBL)
RNPS1 ProteinQ15287 (Uniprot-TrEMBL)
RPL10 ProteinP27635 (Uniprot-TrEMBL)
RPL10A ProteinP62906 (Uniprot-TrEMBL)
RPL11 ProteinP62913 (Uniprot-TrEMBL)
RPL12 ProteinP30050 (Uniprot-TrEMBL)
RPL13 ProteinP26373 (Uniprot-TrEMBL)
RPL13A ProteinP40429 (Uniprot-TrEMBL)
RPL14 ProteinP50914 (Uniprot-TrEMBL)
RPL15 ProteinP61313 (Uniprot-TrEMBL)
RPL17 ProteinP18621 (Uniprot-TrEMBL)
RPL18 ProteinQ07020 (Uniprot-TrEMBL)
RPL18A ProteinQ02543 (Uniprot-TrEMBL)
RPL19 ProteinP84098 (Uniprot-TrEMBL)
RPL21 ProteinP46778 (Uniprot-TrEMBL)
RPL22 ProteinP35268 (Uniprot-TrEMBL)
RPL23 ProteinP62829 (Uniprot-TrEMBL)
RPL23A ProteinP62750 (Uniprot-TrEMBL)
RPL24 ProteinP83731 (Uniprot-TrEMBL)
RPL26 ProteinP61254 (Uniprot-TrEMBL)
RPL26L1 ProteinQ9UNX3 (Uniprot-TrEMBL)
RPL27 ProteinP61353 (Uniprot-TrEMBL)
RPL27A ProteinP46776 (Uniprot-TrEMBL)
RPL28 ProteinP46779 (Uniprot-TrEMBL)
RPL29 ProteinP47914 (Uniprot-TrEMBL)
RPL3 ProteinP39023 (Uniprot-TrEMBL)
RPL30 ProteinP62888 (Uniprot-TrEMBL)
RPL31 ProteinP62899 (Uniprot-TrEMBL)
RPL32 ProteinP62910 (Uniprot-TrEMBL)
RPL34 ProteinP49207 (Uniprot-TrEMBL)
RPL35 ProteinP42766 (Uniprot-TrEMBL)
RPL35A ProteinP18077 (Uniprot-TrEMBL)
RPL36 ProteinQ9Y3U8 (Uniprot-TrEMBL)
RPL36A ProteinP83881 (Uniprot-TrEMBL)
RPL37 ProteinP61927 (Uniprot-TrEMBL)
RPL37A ProteinP61513 (Uniprot-TrEMBL)
RPL38 ProteinP63173 (Uniprot-TrEMBL)
RPL39 ProteinP62891 (Uniprot-TrEMBL)
RPL3L ProteinQ92901 (Uniprot-TrEMBL)
RPL4 ProteinP36578 (Uniprot-TrEMBL)
RPL40 ProteinP62987 (Uniprot-TrEMBL)
RPL41 ProteinP62945 (Uniprot-TrEMBL)
RPL5 ProteinP46777 (Uniprot-TrEMBL)
RPL6 ProteinQ02878 (Uniprot-TrEMBL)
RPL7 ProteinP18124 (Uniprot-TrEMBL)
RPL7A ProteinP62424 (Uniprot-TrEMBL)
RPL8 ProteinP62917 (Uniprot-TrEMBL)
RPL9 ProteinP32969 (Uniprot-TrEMBL)
RPLP0 ProteinP05388 (Uniprot-TrEMBL)
RPLP1 ProteinP05386 (Uniprot-TrEMBL)
RPLP2 ProteinP05387 (Uniprot-TrEMBL)
RPS10 ProteinP46783 (Uniprot-TrEMBL)
RPS11 ProteinP62280 (Uniprot-TrEMBL)
RPS12 ProteinP25398 (Uniprot-TrEMBL)
RPS13 ProteinP62277 (Uniprot-TrEMBL)
RPS14 ProteinP62263 (Uniprot-TrEMBL)
RPS15 ProteinP62841 (Uniprot-TrEMBL)
RPS15A ProteinP62244 (Uniprot-TrEMBL)
RPS16 ProteinP62249 (Uniprot-TrEMBL)
RPS17 ProteinP08708 (Uniprot-TrEMBL)
RPS18 ProteinP62269 (Uniprot-TrEMBL)
RPS19 ProteinP39019 (Uniprot-TrEMBL)
RPS2 ProteinP15880 (Uniprot-TrEMBL)
RPS20 ProteinP60866 (Uniprot-TrEMBL)
RPS21 ProteinP63220 (Uniprot-TrEMBL)
RPS23 ProteinP62266 (Uniprot-TrEMBL)
RPS24 ProteinP62847 (Uniprot-TrEMBL)
RPS25 ProteinP62851 (Uniprot-TrEMBL)
RPS26 ProteinP62854 (Uniprot-TrEMBL)
RPS27 ProteinP42677 (Uniprot-TrEMBL)
RPS27A(77-156) ProteinP62979 (Uniprot-TrEMBL)
RPS28 ProteinP62857 (Uniprot-TrEMBL)
RPS29 ProteinP62273 (Uniprot-TrEMBL)
RPS3 ProteinP23396 (Uniprot-TrEMBL)
RPS3A ProteinP61247 (Uniprot-TrEMBL)
RPS4X ProteinP62701 (Uniprot-TrEMBL)
RPS4Y1 ProteinP22090 (Uniprot-TrEMBL)
RPS5 ProteinP46782 (Uniprot-TrEMBL)
RPS6 ProteinP62753 (Uniprot-TrEMBL)
RPS7 ProteinP62081 (Uniprot-TrEMBL)
RPS8 ProteinP62241 (Uniprot-TrEMBL)
RPS9 ProteinP46781 (Uniprot-TrEMBL)
RPSA ProteinP08865 (Uniprot-TrEMBL)
SMG1 ProteinQ96Q15 (Uniprot-TrEMBL)
SMG1:Phosphorylated

UPF1:EJC:Translated

mRNP		ComplexR-HSA-927890 (Reactome)
SMG1:SMG8:SMG9 ComplexComplexR-HSA-927853 (Reactome)
SMG1:UPF1:EJC:Translated mRNPComplexR-HSA-927767 (Reactome)
SMG5 ProteinQ9UPR3 (Uniprot-TrEMBL)
SMG5ProteinQ9UPR3 (Uniprot-TrEMBL)
SMG6 ProteinQ86US8 (Uniprot-TrEMBL)
SMG6ProteinQ86US8 (Uniprot-TrEMBL)
SMG7 ProteinQ92540 (Uniprot-TrEMBL)
SMG7ProteinQ92540 (Uniprot-TrEMBL)
SMG8 ProteinQ8ND04 (Uniprot-TrEMBL)
SMG9 ProteinQ9H0W8 (Uniprot-TrEMBL)
Translated mRNA

Complex with Premature Termination Codon Not Preceding Exon

Junction		ComplexR-HSA-927787 (Reactome)
Translated mRNA

Complex with Premature Termination Codon Preceding Exon

Junction		ComplexR-HSA-927773 (Reactome)
UPF1 ProteinQ92900 (Uniprot-TrEMBL)
UPF1:eRF3 Complex on Translated mRNAComplexR-HSA-927762 (Reactome)
UPF1ProteinQ92900 (Uniprot-TrEMBL)
UPF2 ProteinQ9HAU5 (Uniprot-TrEMBL)
UPF3A ProteinQ9H1J1 (Uniprot-TrEMBL)
UPF3AS-2 ProteinQ9H1J1-2 (Uniprot-TrEMBL)
UPF3B ProteinQ9BZI7 (Uniprot-TrEMBL)
mRNA Cleaved by SMG6ComplexR-HSA-927845 (Reactome)
p-4S-UPF1 ProteinQ92900 (Uniprot-TrEMBL)
p-4S-UPF1ProteinQ92900 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADPArrowR-HSA-927889 (Reactome)
ATPR-HSA-927889 (Reactome)
Cap Binding Complex (CBC)ArrowR-HSA-927830 (Reactome)
EIF4G1ArrowR-HSA-927830 (Reactome)
PABPC1ArrowR-HSA-927830 (Reactome)
PP2A (Aalpha:B55alpha:Calpha)ArrowR-HSA-927830 (Reactome)
PP2A (Aalpha:B55alpha:Calpha)R-HSA-927813 (Reactome)
PP2A (Aalpha:B55alpha:Calpha)mim-catalysisR-HSA-927830 (Reactome)
Phosphorylated UPF1:SMG5:SMG7:SMG6:PP2A:Translated mRNPArrowR-HSA-927813 (Reactome)
Phosphorylated UPF1:SMG5:SMG7:SMG6:PP2A:Translated mRNPR-HSA-927836 (Reactome)
Phosphorylated UPF1:SMG5:SMG7:SMG6:PP2A:Translated mRNPmim-catalysisR-HSA-927836 (Reactome)
R-HSA-927789 (Reactome) Nonsense-mediated decay of an mRNA can be triggered even if the termination codon does not precede an exon junction (Buhler et al. 2006, Eberle et al. 2008, Silva et al. 2008, Singh et al. 2008, Ivanov et al. 2008). UPF1 and PABP seem to modulate the efficiency of translation termination and PABP in the proximity of a termination codon prevents NMD likely by outcompeting UPF1 for interaction with eRF3 (Singh et al. 2008, Ivanov et al. 2008, Silva et al. 2008). Factors in the competition may be the length and secondary structure of the 3' UTR (Buhler et al. 2006, Eberle et al. 2008). UPF1 preferentially binds some but not all longer UTRs (Hogg and Goff 2010).
Interaction of eRF3 with PABP stimulates ribosome dissociation and initiation of a new round of translation on the mRNA. Interaction of eRF3 with UPF1 appears to promote nonsense-mediated decay. It is possible but not yet demonstrated that all components of the SURF complex (SMG1, UPF1, eRF1, eRF3) are assembled on an mRNA without an exon junction complex and that UPF1 is phosphorylated by SMG1.
R-HSA-927813 (Reactome) SMG6, SMG5 and SMG7 contain 14-3-3 domains which are believed to bind phosphorylated SQ motifs in UPF1 (Chiu et al. 2003, Ohnishi et al. 2003, Unterholzner and Izaurralde 2004, Fukuhara et al. 2005, Durand et al. 2007). SMG7 has been shown to bind UPF1 directly, target UPF1 for dephosphorylation by PP2A, and recruit enzymes that degrade RNA (Ohnishi et al. 2003, Unterholzner and Izaurralde 2004, Fukuhara et al. 2005). UPF3AS (the small isoform of UPF3A) also associates with the complex (Ohnishi et al. 2003). SMG6 is an endoribonuclease that cleaves the mRNA bound by UPF1 and also recruits phosphatase PP2A to dephosphorylate UPF1 (Chiu et al. 2003, Glavan et al. 2006, Eberle et al. 2009) .
Though immunofluorescence in vivo indicates that SMG5 and SMG7 exist in separate complexes from SMG6 (Unterholzner and Izaurralde 2004) immunoprecipitation shows that SMG6 is present in complexes that also contain SMG5, SMG7, UPF1, UPF2, Y14, Magoh, and PABP (Kashima et al. 2010). SMG5, SMG6, and SMG7 are therefore represented here together in the same RNP complex. It is possible that some complexes contain only SMG6 or SMG5:SMG7 (reviewed in Nicholson et al. 2010, Muhlemann and Lykke-Andersen 2010). Note that "Smg5/7a" in Chiu et al. 2003 actually refers to SMG6.
Phosphorylated UPF1 also inhibits translation initiation by inhibiting conversion of 40S:tRNAmet:mRNA to 80S:tRNAmet:mRNA complexes (Isken et al. 2008)
R-HSA-927830 (Reactome) SMG6 endonucleolytically cleaves an mRNA it is believed that the resulting fragments are degraded by exonucleases, possibly XRN1, a 5'-to-3' nuclease, and the exosome complex, a 3'-to-5' nuclease (Huntzinger et al. 2008, Eberle et al. 2009). Inhibition of XRN1 is observed to cause accumulation of SMG6-cleaved intermediates therefore XRN1 is postulated to act downstream of SMG6 (Huntzinger et al. 2008).
In general, during Nonsense-Mediated Decay mRNAs are observed to be deadenlyated (implicating the PAN2 complex, PARN complex, and CCR4 complex), decapped (implicating the DCP1:DCP2 complex), and exoribonucleolytically digested (implicating the XRN1 5'-to-3' exonuclease and exosome 3'-to-5' exonuclease) (Lykke-Andersen 2002, Chen et al. 2003, Lejeune et al. 2003, Couttet and Grange 2004, Unterholzner and Izaurralde 2004, Yamashita et al. 2005). UPF1 is observed to associate with the decapping enzymes DCP1a and DCP2, however the specific decay reactions that occur after SMG6, SMG5 and SMG7 have associated with an mRNA are unknown (Lykke-Andersen et al. 2002). Likewise, SMG6 may be present in complexes separate from SMG5 and SMG7 and these complexes may have different routes of decay (reviewed in Nicholson et al. 2010, Muhlemann and Lykke-Andersen 2010).
ATPase activity of UPF1 is necessary for NMD and may reflect ATP-dependent helicase activity that disassembles the mRNA-protein complex (Franks et al. 2010). UPF1 must be dephosphorylated by PP2A for NMD to continue (Ohnishi et al. 2003, Chiu et al. 2003). Presumably the dephosphoryation recycles UPF1 for interaction with other mRNA complexes.
R-HSA-927832 (Reactome) The presence of an exon junction complex (EJC) downstream of a termination codon enhances nonsense-mediated decay (NMD) but is not absolutely required for NMD. The EJC is deposited during splicing and remains bound to the mRNA until a ribosome dislodges it during the pioneer round of translation, distinguished by the presence of the cap-binding complex at the 5' end. If translation terminates at least 50-55 nucleotides 5' to an EJC during the pioneer round then termination factors (eRF1 and eRF3) and the EJC recruit UPF1 and other NMD machinery (Lykke-Andersen et al. 2001, Ishigaki et al. 2001, Le Hir et al. 2001, Gehring et al. 2003, Hosoda et al. 2005, Kashima et al. 2006, Singh et al. 2007, Chamieh et al. 2008, Ivanov et al. 2008, Buchwald et al. 2010).
A current model for NMD enhanced by the EJC posits recruitment of UPF1, SMG1, SMG8, and SMG9 to eRF3 at the ribosome to form the SURF complex (Kashima et al. 2006, Chang et al. 2007, Isken et al. 2008, Muhlemann et al. 2008, Stalder and Muhlemann 2008, Chamieh et al. 2009, Maquat and Gong 2009, Rebbapragada and Lykke-Andersen 2009, Hwang et al. 2010, Nicholson et al. 2010). UPF1 and SMG1 then interact with components of the EJC, activating phosphorylation of UPF1 by SMG1.
The model of the NMD mechanism is inferred from known protein interactions:
eRF1 and eRF3 interact with UPF1, the key regulator of NMD which also binds SMG1, UPF2, and UPF3 (UPF3a or UPF3b) to form the SURF complex (Kashima et al.2006, Ivanov et al. 2008, Clerici et al. 2009, Chakrabarti et al. 2011). UPF1 also interacts with CBP80 at the cap of the mRNA (Hwang et al. 2010).
SMG8 and SMG9 associate with SMG1 and the SURF complex and modulate the phosphorylation activity of SMG1 (Yamashita et al. 2009).
UPF2 and UPF3 are peripheral components of the EJC and thus may link the EJC to the SURF complex (Chamieh et al. 2008). UPF3b binds UPF1 and a composite surface formed by the Y14, MAGOH, and eIF4A3 subunits of the core EJC (Gehring et al. 2003, Kunz et al. 2006, Buchwald et al. 2010). SMG1 also interacts with the EJC (Kashima et al. 2006, Yamashita et al. 2009). UPF3a more weakly activates NMD than does UPF3b (Kunz et al. 2006) and UPF3a levels increase in response to loss of UPF3b (Chan et al. 2009).
The binding of UPF1 to translated RNAs may occur in two steps: Binding of the SURF complex to the terminating ribosome followed by transfer of UPF1 and SMG1 to the EJC (Kashima et al. 2006, Hwang et al. 2010).
The core EJC (Y14, MAGOH, eIF4A3, and BTZ) can activate NMD without UPF2, however RNPS1, another EJC subunit, requires UPF2 to activate NMD (Gehring et al. 2005). RNAs show differential dependence on RNPS1-activated NMD (Gehring et al. 2005). Also, NMD of some transcripts requires EJC component eIF4A3 but not UPF3b (Chan et al. 2007) therefore there may be more than one route to activating NMD via the EJC.
R-HSA-927836 (Reactome) SMG6 is an endoribonuclease which cleaves the mRNA bound by UPF1 near the premature termination codon (Glavan et al. 2006, Eberle et al. 2009).
R-HSA-927889 (Reactome) SMG1 phosphorylates UPF1 in vitro and in vivo (Denning et al. 2001, Yamashita et al. 2001, Kashima et al. 2006). Serines 1073, 1078, 1096, and 1116 in isoform 2 (Serines 1084, 1089, 1107, 1127 in isoform 1) are phosphorylated in vitro and phosphorylation at serines 1078 and 1096 has been confirmed in vivo (Yamashita et al. 2001, Ohnishi et al. 2003, Kashima et al. 2006). UPF1 also contains additional serine and threonine residues that could be phosphorylated. SMG8 and SMG9 associate with SMG1 and regulate the kinase activity of SMG1 (Yamashita et al. 2009). The phosphorylation reaction is rate-limiting in nonsense-mediated decay and is therefore regarded as a licensing step (reviewed in Rebbapragada and Lykke-Andersen 2009). Phosphorylation is enhanced by the exon junction complex, which can interact with UPF1 via UPF2 and/or UPF3 (Kashima et al. 2006, Ivanov et al. 2008) or via Y14:Magoh (Ivanov et al. 2008). SMG8 and SMG9 bind SMG1 and regulate its kinase activity (Yamashita et al. 2009, Fernandez et al. 2011).
SMG1:Phosphorylated

UPF1:EJC:Translated

mRNP		ArrowR-HSA-927889 (Reactome)
SMG1:Phosphorylated

UPF1:EJC:Translated

mRNP		R-HSA-927813 (Reactome)
SMG1:SMG8:SMG9 ComplexR-HSA-927832 (Reactome)
SMG1:UPF1:EJC:Translated mRNPArrowR-HSA-927832 (Reactome)
SMG1:UPF1:EJC:Translated mRNPR-HSA-927889 (Reactome)
SMG1:UPF1:EJC:Translated mRNPmim-catalysisR-HSA-927889 (Reactome)
SMG5ArrowR-HSA-927830 (Reactome)
SMG5R-HSA-927813 (Reactome)
SMG6ArrowR-HSA-927830 (Reactome)
SMG6R-HSA-927813 (Reactome)
SMG7ArrowR-HSA-927830 (Reactome)
SMG7R-HSA-927813 (Reactome)
Translated mRNA

Complex with Premature Termination Codon Not Preceding Exon

Junction		R-HSA-927789 (Reactome)
Translated mRNA

Complex with Premature Termination Codon Preceding Exon

Junction		R-HSA-927832 (Reactome)
UPF1:eRF3 Complex on Translated mRNAArrowR-HSA-927789 (Reactome)
UPF1ArrowR-HSA-927830 (Reactome)
UPF1R-HSA-927789 (Reactome)
UPF1R-HSA-927832 (Reactome)
mRNA Cleaved by SMG6ArrowR-HSA-927836 (Reactome)
mRNA Cleaved by SMG6R-HSA-927830 (Reactome)
p-4S-UPF1mim-catalysisR-HSA-927830 (Reactome)
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