Nonsense-Mediated Decay (NMD) (Homo sapiens)

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7, 9, 22, 23, 30...15, 41, 5114, 27, 37, 41, 46...17, 19, 34, 36, 53...1, 11, 16, 23, 24, 45...2-7, 10, 12...8, 14, 15, 18, 21...Nonsense-mediated Decay Enhanced by the Exon Junction ComplexcytosolNonsense-mediated Decay Independent of the Exon Junction ComplexRPS8 RPL35A SMG9 RPS17 RPL21 EIF4G1 RPS27 RPL14 RPL36A RPS16 PPP2R1A RPL27 18S rRNA RPL18A RPL19 UPF3A RPL35A RPS15 RPL31 RPL12 RPL27A RPL13A RPL41 RPL24 RPL28 CASC3 SMG1 SMG8 GDP RPL6 5' Fragment of Cleaved mRNA RPL17 RPL40 RPL23 RPL13 5S rRNA RPL17 RPS6 RPL19 RPS13 RPS18 RPL39 RPS20 SMG1:SMG8:SMG9ComplexUPF1 RPL31 RPL13A RPL8 ATPRBM8A RPS29 RPL40 RPL34 mRNA Cleaved by SMG6RNPS1 SMG7 RPS21 28S rRNA RPL4 RPL24 RPL4 RPS15 ADPRPS13 UPF3B RPS15 RPS9 RPS26 RPS2 RPL28 RPL40 RPL32 UPF2 RPL24 RPS10 MAGOH RPS20 PABPC1RPL30 RPS29 GDP PP2A(Aalpha:B55alpha:Calpha)RPS5 RPL13A RPS12 RPS4X SMG5 RPL32 RPS28 RPS7 RPS25 Cap Binding Complex(CBC)NCBP2 SMG1:PhosphorylatedUPF1:EJC:TranslatedmRNPFAU RPLP2 RPS19 5.8S rRNA PPP2R2A RPL19 RPS18 NCBP2 RPL30 RPS15A RPS24 ETF1 GSPT2 PABPC1 18S rRNA RPL11 RPL23A RPS29 NCBP2 RPS27 RPLP0 UPF3B RPL5 RPL37A RPS20 RPL4 RPS24 RPL36 SMG1 RPLP0 RPS13 RPS13 mRNA with premature termination codon preceding exon junction RPL36 RPLP2 RPL10 SMG6 RPS4X PABPC1 SMG9 RPS24 RPL22 RPLP2 RPL31 RPL31 RPL37A RPS27A(77-156) RPL7 SMG6RPS4Y1 RPL17 RPL3L RPS3A RPS8 RPL35A RPS10 RBM8A RPL31 RPL12 RPS16 RNPS1 GSPT2 RPL12 RPS6 mRNA with premature termination codon preceding exon junction EIF4A3 RPLP1 RPL10 CASC3 RPS3A RPS4X RPL6 RPL27 RPL32 p-4S-UPF1 RPS18 RPS19 RPL41 RPL36 RPL35 RPS27A(77-156) RPL19 GDP RPLP2 GDP RPL3L RPL10 FAU RPL21 RPS4X RPL9 NCBP1 SMG8 PPP2CA RPS4X RPS4Y1 RPS27A(77-156) RPS19 RPL36A RPS4Y1 RPS11 RPL10 RPL38 RPL26 PABPC1 RPL12 RPL38 RPS25 RPLP2 RPL29 RPL39 RPL13 RPS4Y1 UPF3B RPS7 NCBP1 RPL7 RPL39 SMG5RPL10A RPS3 tRNA RPL7 RPL18 NCBP2 RPS28 RPS26 UPF3B RPS3 RPS15A SMG8 RPS10 Translated mRNAComplex withPrematureTermination CodonPreceding ExonJunction18S rRNA RPL18A RPL34 RPL32 RPSA 5.8S rRNA tRNA RPS6 RPL11 RPL27A RPS15A RPL26 RPS11 RPL11 RPL15 UPF2 RPS12 RPS29 RPS15 RPL10 RPL36A RPL10A RPL39 RPS3 RPL30 RPLP0 RPL13A RPL26 RPL5 RPL11 RPL22 RPS29 RPS20 UPF3A RPS8 RPL26L1 PPP2R1A RPS5 RPS14 FAU RPL35 RPL10A RPSA RPS9 RPS5 RPL26L1 RPL36A RPS16 RPL15 RPS21 RPL17 RPS14 RPS18 RPL13 RPSA mRNA with premature termination codon not preceding exon junction RPL7A RPL37 RPL34 RPL9 RPL36 MAGOH RPL14 RPS2 RPS16 RNPS1 RPLP1 RPL8 RPS9 RPLP1 RPL21 RPS9 RPL37 RPS17 5S rRNA SMG7 RPLP0 RPL18A RPL3 RPL18 RPL24 UPF1 RPL41 RPL37A p-4S-UPF1NCBP1 RPL36A RPS25 RPL23 RPS23 mRNA with premature termination codon preceding exon junction RPL9 RPL27A RPL29 RPS15 RPL26L1 RPS7 RPL37 RPL7A RPS13 RPS7 RPS15 RPL28 RPS5 RPS19 RPL18 5.8S rRNA RPL35A RPL18A RPL6 RPL34 RPS8 RPL11 RPL24 RPS12 RPS2 ETF1 RPS26 RPL3 RPL23A RPL38 RPL21 EIF4G1 ETF1 RPL26L1 RPL36 SMG9 5.8S rRNA p-4S-UPF1 EIF4A3 NCBP1 RPL23 RPL29 RPL30 RPL22 RPL40 PPP2CA 5.8S rRNA RPS4Y1 RPL15 RPL19 28S rRNA RPS10 RPL9 RPS26 RPL23 RPS25 SMG6 RPL3L RPS24 RPS11 RPS24 FAU RPL13 RPS3A 5S rRNA RPS19 RBM8A RPL3 NCBP2 RPL29 RPLP0 RPL18 RPL9 RPL17 RPS17 RPS6 PABPC1 RPL22 UPF2 RPL29 RPS18 mRNA with premature termination codon preceding exon junction RPL12 UPF3A RPS15A CASC3 RPS12 RPS11 RPS4Y1 MAGOH RPL37A EIF4G1 RPL4 RPS14 RPS25 RPL40 RPL3 RPL35 RPS17 RPS13 RPS2 RPL27A RPS10 RPL21 RPL13A RPL37 RPL7A Translated mRNAComplex withPrematureTermination CodonNot Preceding ExonJunctionRPL4 RPL27 RPL23A RPL6 RPL5 RPL19 RPL3 EIF4A3 RPLP2 RPL31 RPL32 tRNA RPL23A RPS3A RPS26 RPL13 RPL41 RPL8 RPL22 18S rRNA RPL28 RPL11 RPSA RPL34 28S rRNA RPL7A RPL38 NCBP1 RPL35A RPL3L RPS27A(77-156) RPL35A RPS27 ETF1 PABPC1 RPS28 RPS23 tRNA RPS23 5.8S rRNA RPL35 RPL15 SMG7RPL8 RPL14 RPL30 RPS9 RPL6 RPL28 RPL8 RPS23 28S rRNA RPSA RPL9 RPL18 18S rRNA 5S rRNA 18S rRNA RPS29 RPL36 RPS3 RPL15 UPF3AS-2 RPL13 PABPC1 RPL4 3' Fragment of Cleaved mRNA p-4S-UPF1 RPS27 RPS25 RPS7 RPL28 RPL27 RPS16 RPS26 RPS2 UPF1:eRF3 Complex onTranslated mRNANCBP1 UPF1RPS8 RPL35 RPL36A ETF1 GSPT2 RBM8A RPL27A RPL23 RPL24 RPL10 RPL38 RPL5 EIF4G1 NCBP2 RPL10A RPS27A(77-156) RPL27A 28S rRNA RPLP1 RPS18 RPL3 NCBP2 RPS11 GDP RPL21 tRNA RPL27 RPL38 RPS2 RPL39 RPSA RPS3 RPS27A(77-156) RPL14 NCBP2 RPL29 RPL8 RPL37A SMG1:UPF1:EJC:Translated mRNPRPL40 PPP2R2A SMG5 RPL12 RPL32 RPS28 RPL39 PPP2CA RPS27 RPS3A EIF4G1 RPS9 RPL26 tRNA PhosphorylatedUPF1:SMG5:SMG7:SMG6:PP2A:Translated mRNPRPS3 RPL27 RPS5 CASC3 SMG1 GSPT2 EIF4A3 RPL26 RPL5 RPL23A RPS12 5S rRNA RPS6 RPLP1 EIF4G1 RPS19 RPS15A RPL13A FAU RPS16 RPL10A RPS14 RPL15 RPL14 RPS20 RPS17 UPF2 FAU RPL7A 5S rRNA PPP2R2A RPL23 mRNA with premature termination codon not preceding exon junction GSPT2 RPL17 RPL37 RPL3L RPS7 RPL41 RPS21 GDP RPL5 RPL3L NCBP1 RPS14 RPS11 RPL26 28S rRNA RPS20 RPL22 RPS8 GSPT2 RPS24 RPS4X RPL7 RPL37A RPS23 RPL7 RPS21 RPL18 ETF1 RPL34 RPS21 RPLP1 RPL7A RPL7 RPS3A RPL18A RPL23A RPS10 RPL10A RPL35 RPL6 RPS28 RPS12 RPS23 RPS5 UPF3A EIF4G1RPS15A PABPC1 MAGOH RPLP0 RPL37 RPS28 RPL41 NCBP1 RNPS1 PPP2R1A RPL30 RPS6 RPS21 RPS17 RPL26L1 RPL18A RPS27 RPS14 RPL14 RPL26L1 EIF4G1 1449, 574519


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. View original pathway at: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)
3' Fragment of Cleaved mRNA R-NUL-927738 (Reactome)
5' Fragment of Cleaved mRNA R-NUL-927835 (Reactome)
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)
mRNA with premature termination codon not preceding exon junction R-NUL-927733 (Reactome)
mRNA with premature termination codon preceding exon junction R-NUL-927796 (Reactome) This is an mRNA with a premature termination codon which precedes an exon junction. Such mRNAs are subject to nonsense-mediated decay (NMD).
p-4S-UPF1 ProteinQ92900 (Uniprot-TrEMBL)
p-4S-UPF1ProteinQ92900 (Uniprot-TrEMBL)
tRNA R-HSA-141679 (Reactome)

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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