Nonsense-Mediated Decay (NMD) (Homo sapiens)
From WikiPathways
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.Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=927802
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.Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=927802
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History
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External references
DataNodes
| View all... |
| Name | Type | Database reference | Comment |
|---|---|---|---|
| 18S rRNA [cytosol] | Protein | X03205 (EMBL)  | |
| 28S rRNA [cytosol] | Protein | M11167 (EMBL) | |
| 5.8S rRNA [cytosol] | Protein | J01866 (EMBL) | |
| 5S rRNA [cytosol] | Protein | V00589 (EMBL) | |
| ADP | Metabolite | CHEBI:16761 (ChEBI) | |
| ATP | Metabolite | CHEBI:15422 (ChEBI) | |
| CASC3 [cytosol] | Protein | O15234 (Uniprot-TrEMBL) | |
| Cap Binding Complex (CBC) | Complex | REACT_3506 (Reactome) | |
| EIF4A3 [cytosol] | Protein | P38919 (Uniprot-TrEMBL) | |
| EIF4G1 [cytosol] | Protein | Q04637 (Uniprot-TrEMBL) | |
| EIF4G1 | Protein | Q04637 (Uniprot-TrEMBL) | |
| ETF1 [cytosol] | Protein | P62495 (Uniprot-TrEMBL) | |
| FAU [cytosol] | Protein | P62861 (Uniprot-TrEMBL) | |
| GDP [cytosol] | Metabolite | CHEBI:17552 (ChEBI) | |
| GSPT2 [cytosol] | Protein | Q8IYD1 (Uniprot-TrEMBL) | |
| MAGOH [cytosol] | Protein | P61326 (Uniprot-TrEMBL) | |
| NCBP1 [cytosol] | Protein | Q09161 (Uniprot-TrEMBL) | |
| NCBP2 [cytosol] | Protein | P52298 (Uniprot-TrEMBL) | |
| PABPC1 [cytosol] | Protein | P11940 (Uniprot-TrEMBL) | |
| PABPC1 | Protein | P11940 (Uniprot-TrEMBL) | |
| PP2A (Aalpha:B55alpha:Calpha) | Complex | REACT_76435 (Reactome) | |
| PPP2CA [cytosol] | Protein | P67775 (Uniprot-TrEMBL) | |
| PPP2R1A(2-589) [cytosol] | Protein | P30153 (Uniprot-TrEMBL) | |
| PPP2R2A(2-447) [cytosol] | Protein | P63151 (Uniprot-TrEMBL) | |
| Phosphorylated
UPF1:SMG5:SMG7:SMG6:PP2A:Translated mRNP | Complex | REACT_76275 (Reactome) | |
| RBM8A [cytosol] | Protein | Q9Y5S9 (Uniprot-TrEMBL) | |
| RNPS1 [cytosol] | Protein | Q15287 (Uniprot-TrEMBL) | |
| RPL10 [cytosol] | Protein | P27635 (Uniprot-TrEMBL) | |
| RPL10A [cytosol] | Protein | P62906 (Uniprot-TrEMBL) | |
| RPL11 [cytosol] | Protein | P62913 (Uniprot-TrEMBL) | |
| RPL12 [cytosol] | Protein | P30050 (Uniprot-TrEMBL) | |
| RPL13(2-211) [cytosol] | Protein | P26373 (Uniprot-TrEMBL) | |
| RPL13A [cytosol] | Protein | P40429 (Uniprot-TrEMBL) | |
| RPL14 [cytosol] | Protein | P50914 (Uniprot-TrEMBL) | |
| RPL15(2-204) [cytosol] | Protein | P61313 (Uniprot-TrEMBL) | |
| RPL17 [cytosol] | Protein | P18621 (Uniprot-TrEMBL) | |
| RPL18 [cytosol] | Protein | Q07020 (Uniprot-TrEMBL) | |
| RPL18A [cytosol] | Protein | Q02543 (Uniprot-TrEMBL) | |
| RPL19 [cytosol] | Protein | P84098 (Uniprot-TrEMBL) | |
| RPL21 [cytosol] | Protein | P46778 (Uniprot-TrEMBL) | |
| RPL22 [cytosol] | Protein | P35268 (Uniprot-TrEMBL) | |
| RPL23 [cytosol] | Protein | P62829 (Uniprot-TrEMBL) | |
| RPL23A [cytosol] | Protein | P62750 (Uniprot-TrEMBL) | |
| RPL24 [cytosol] | Protein | P83731 (Uniprot-TrEMBL) | |
| RPL26 [cytosol] | Protein | P61254 (Uniprot-TrEMBL) | |
| RPL26L1(2-145) [cytosol] | Protein | Q9UNX3 (Uniprot-TrEMBL) | |
| RPL27(2-136) [cytosol] | Protein | P61353 (Uniprot-TrEMBL) | |
| RPL27A [cytosol] | Protein | P46776 (Uniprot-TrEMBL) | |
| RPL28 [cytosol] | Protein | P46779 (Uniprot-TrEMBL) | |
| RPL29 [cytosol] | Protein | P47914 (Uniprot-TrEMBL) | |
| RPL3 [cytosol] | Protein | P39023 (Uniprot-TrEMBL) | |
| RPL30(2-115) [cytosol] | Protein | P62888 (Uniprot-TrEMBL) | |
| RPL31 [cytosol] | Protein | P62899 (Uniprot-TrEMBL) | |
| RPL32 [cytosol] | Protein | P62910 (Uniprot-TrEMBL) | |
| RPL34 [cytosol] | Protein | P49207 (Uniprot-TrEMBL) | |
| RPL35 [cytosol] | Protein | P42766 (Uniprot-TrEMBL) | |
| RPL35A [cytosol] | Protein | P18077 (Uniprot-TrEMBL) | |
| RPL36 [cytosol] | Protein | Q9Y3U8 (Uniprot-TrEMBL) | |
| RPL36A [cytosol] | Protein | P83881 (Uniprot-TrEMBL) | |
| RPL37 [cytosol] | Protein | P61927 (Uniprot-TrEMBL) | |
| RPL37A [cytosol] | Protein | P61513 (Uniprot-TrEMBL) | |
| RPL38 [cytosol] | Protein | P63173 (Uniprot-TrEMBL) | |
| RPL39 [cytosol] | Protein | P62891 (Uniprot-TrEMBL) | |
| RPL3L(2-407) [cytosol] | Protein | Q92901 (Uniprot-TrEMBL) | |
| RPL4 [cytosol] | Protein | P36578 (Uniprot-TrEMBL) | |
| RPL41 [cytosol] | Protein | P62945 (Uniprot-TrEMBL) | |
| RPL5 [cytosol] | Protein | P46777 (Uniprot-TrEMBL) | |
| RPL6 [cytosol] | Protein | Q02878 (Uniprot-TrEMBL) | |
| RPL7 [cytosol] | Protein | P18124 (Uniprot-TrEMBL) | |
| RPL7A [cytosol] | Protein | P62424 (Uniprot-TrEMBL) | |
| RPL8 [cytosol] | Protein | P62917 (Uniprot-TrEMBL) | |
| RPL9 [cytosol] | Protein | P32969 (Uniprot-TrEMBL) | |
| RPLP0 [cytosol] | Protein | P05388 (Uniprot-TrEMBL) | |
| RPLP1(2-114) [cytosol] | Protein | P05386 (Uniprot-TrEMBL) | |
| RPLP2 [cytosol] | Protein | P05387 (Uniprot-TrEMBL) | |
| RPS10 [cytosol] | Protein | P46783 (Uniprot-TrEMBL) | |
| RPS11 [cytosol] | Protein | P62280 (Uniprot-TrEMBL) | |
| RPS12 [cytosol] | Protein | P25398 (Uniprot-TrEMBL) | |
| RPS13(2-151) [cytosol] | Protein | P62277 (Uniprot-TrEMBL) | |
| RPS14 [cytosol] | Protein | P62263 (Uniprot-TrEMBL) | |
| RPS15 [cytosol] | Protein | P62841 (Uniprot-TrEMBL) | |
| RPS15A [cytosol] | Protein | P62244 (Uniprot-TrEMBL) | |
| RPS16 [cytosol] | Protein | P62249 (Uniprot-TrEMBL) | |
| RPS17 [cytosol] | Protein | P08708 (Uniprot-TrEMBL) | |
| RPS18 [cytosol] | Protein | P62269 (Uniprot-TrEMBL) | |
| RPS19 [cytosol] | Protein | P39019 (Uniprot-TrEMBL) | |
| RPS2(2-293) [cytosol] | Protein | P15880 (Uniprot-TrEMBL) | |
| RPS20 [cytosol] | Protein | P60866 (Uniprot-TrEMBL) | |
| RPS21 [cytosol] | Protein | P63220 (Uniprot-TrEMBL) | |
| RPS23 [cytosol] | Protein | P62266 (Uniprot-TrEMBL) | |
| RPS24 [cytosol] | Protein | P62847 (Uniprot-TrEMBL) | |
| RPS25 [cytosol] | Protein | P62851 (Uniprot-TrEMBL) | |
| RPS26 [cytosol] | Protein | P62854 (Uniprot-TrEMBL) | |
| RPS27 [cytosol] | Protein | P42677 (Uniprot-TrEMBL) | |
| RPS27A(77-156) [cytosol] | Protein | P62979 (Uniprot-TrEMBL) | |
| RPS28 [cytosol] | Protein | P62857 (Uniprot-TrEMBL) | |
| RPS29 [cytosol] | Protein | P62273 (Uniprot-TrEMBL) | |
| RPS3 [cytosol] | Protein | P23396 (Uniprot-TrEMBL) | |
| RPS3A [cytosol] | Protein | P61247 (Uniprot-TrEMBL) | |
| RPS4X [cytosol] | Protein | P62701 (Uniprot-TrEMBL) | |
| RPS4Y1(2-263) [cytosol] | Protein | P22090 (Uniprot-TrEMBL) | |
| RPS5(1-204) [cytosol] | Protein | P46782 (Uniprot-TrEMBL) | |
| RPS6 [cytosol] | Protein | P62753 (Uniprot-TrEMBL) | |
| RPS7 [cytosol] | Protein | P62081 (Uniprot-TrEMBL) | |
| RPS8(2-208) [cytosol] | Protein | P62241 (Uniprot-TrEMBL) | |
| RPS9 [cytosol] | Protein | P46781 (Uniprot-TrEMBL) | |
| RPSA [cytosol] | Protein | P08865 (Uniprot-TrEMBL) | |
| SMG1(1-3657) [cytosol] | Protein | Q96Q15 (Uniprot-TrEMBL) | |
| SMG1:Phosphorylated
UPF1:EJC:Translated mRNP | Complex | REACT_76156 (Reactome) | |
| SMG1:SMG8:SMG9 Complex | Complex | REACT_76062 (Reactome) | |
| SMG1:UPF1:EJC:Translated mRNP | Complex | REACT_76647 (Reactome) | |
| SMG5 [cytosol] | Protein | Q9UPR3 (Uniprot-TrEMBL) | |
| SMG5 | Protein | Q9UPR3 (Uniprot-TrEMBL) | |
| SMG6 [cytosol] | Protein | Q86US8 (Uniprot-TrEMBL) | |
| SMG6 | Protein | Q86US8 (Uniprot-TrEMBL) | |
| SMG7 [cytosol] | Protein | Q92540 (Uniprot-TrEMBL) | |
| SMG7 | Protein | Q92540 (Uniprot-TrEMBL) | |
| SMG8 [cytosol] | Protein | Q8ND04 (Uniprot-TrEMBL) | |
| SMG9(1-520) [cytosol] | Protein | Q9H0W8 (Uniprot-TrEMBL) | |
| Translated mRNA
Complex with Premature Termination Codon Not Preceding Exon Junction | Complex | REACT_76767 (Reactome) | |
| Translated mRNA
Complex with Premature Termination Codon Preceding Exon Junction | Complex | REACT_76510 (Reactome) | |
| UBA52(77-128) [cytosol] | Protein | P62987 (Uniprot-TrEMBL) | |
| UPF1 [cytosol] | Protein | Q92900 (Uniprot-TrEMBL) | |
| UPF1:eRF3 Complex on Translated mRNA | Complex | REACT_76212 (Reactome) | |
| UPF1 | Protein | Q92900 (Uniprot-TrEMBL) | |
| UPF2 [cytosol] | Protein | Q9HAU5 (Uniprot-TrEMBL) | |
| UPF3A [cytosol] | Protein | Q9H1J1 (Uniprot-TrEMBL) | |
| UPF3AS-2 [cytosol] | Protein | Q9H1J1-2 (Uniprot-TrEMBL) | |
| UPF3B [cytosol] | Protein | Q9BZI7 (Uniprot-TrEMBL) | |
| mRNA Cleaved by SMG6 | Complex | REACT_76273 (Reactome) | |
| p-3S1089,S1107-UPF1 [cytosol] | Protein | Q92900 (Uniprot-TrEMBL) | |
| p-3S1089,S1107-UPF1 | Protein | Q92900 (Uniprot-TrEMBL) | |
| tRNA [cytosol] | Metabolite | CHEBI:17843 (ChEBI) |
Annotated Interactions
| View all... |
| Source | Target | Type | Database reference | Comment |
|---|---|---|---|---|
| ADP | Arrow | REACT_75910 (Reactome) | ||
| ATP | REACT_75910 (Reactome) | |||
| Cap Binding Complex (CBC) | Arrow | REACT_75794 (Reactome) | ||
| EIF4G1 | Arrow | REACT_75794 (Reactome) | ||
| PABPC1 | Arrow | REACT_75794 (Reactome) | ||
| PP2A (Aalpha:B55alpha:Calpha) | Arrow | REACT_75794 (Reactome) | ||
| PP2A (Aalpha:B55alpha:Calpha) | REACT_75891 (Reactome) | |||
| PP2A (Aalpha:B55alpha:Calpha) | mim-catalysis | REACT_75794 (Reactome) | ||
| Phosphorylated
UPF1:SMG5:SMG7:SMG6:PP2A:Translated mRNP | Arrow | REACT_75891 (Reactome) | ||
| Phosphorylated
UPF1:SMG5:SMG7:SMG6:PP2A:Translated mRNP | REACT_75787 (Reactome) | |||
| Phosphorylated
UPF1:SMG5:SMG7:SMG6:PP2A:Translated mRNP | mim-catalysis | REACT_75787 (Reactome) | ||
| REACT_75753 (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. | |||
| REACT_75787 (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). | |||
| REACT_75794 (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. | |||
| REACT_75891 (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) | |||
| REACT_75910 (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). | |||
| REACT_75917 (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. | |||
| SMG1:Phosphorylated
UPF1:EJC:Translated mRNP | Arrow | REACT_75910 (Reactome) | ||
| SMG1:Phosphorylated
UPF1:EJC:Translated mRNP | REACT_75891 (Reactome) | |||
| SMG1:SMG8:SMG9 Complex | REACT_75753 (Reactome) | |||
| SMG1:UPF1:EJC:Translated mRNP | Arrow | REACT_75753 (Reactome) | ||
| SMG1:UPF1:EJC:Translated mRNP | REACT_75910 (Reactome) | |||
| SMG1:UPF1:EJC:Translated mRNP | mim-catalysis | REACT_75910 (Reactome) | ||
| SMG5 | Arrow | REACT_75794 (Reactome) | ||
| SMG5 | REACT_75891 (Reactome) | |||
| SMG6 | Arrow | REACT_75794 (Reactome) | ||
| SMG6 | REACT_75891 (Reactome) | |||
| SMG7 | Arrow | REACT_75794 (Reactome) | ||
| SMG7 | REACT_75891 (Reactome) | |||
| Translated mRNA
Complex with Premature Termination Codon Not Preceding Exon Junction | REACT_75917 (Reactome) | |||
| Translated mRNA
Complex with Premature Termination Codon Preceding Exon Junction | REACT_75753 (Reactome) | |||
| UPF1:eRF3 Complex on Translated mRNA | Arrow | REACT_75917 (Reactome) | ||
| UPF1 | Arrow | REACT_75794 (Reactome) | ||
| UPF1 | REACT_75753 (Reactome) | |||
| UPF1 | REACT_75917 (Reactome) | |||
| mRNA Cleaved by SMG6 | Arrow | REACT_75787 (Reactome) | ||
| mRNA Cleaved by SMG6 | REACT_75794 (Reactome) | |||
| p-3S1089,S1107-UPF1 | mim-catalysis | REACT_75794 (Reactome) |
