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.
Chan WK, Bhalla AD, Le Hir H, Nguyen LS, Huang L, Gécz J, Wilkinson MF.; ''A UPF3-mediated regulatory switch that maintains RNA surveillance.''; PubMedEurope PMCScholia
Eberle AB, Lykke-Andersen S, Mühlemann O, Jensen TH.; ''SMG6 promotes endonucleolytic cleavage of nonsense mRNA in human cells.''; PubMedEurope PMCScholia
Mühlemann O, Lykke-Andersen J.; ''How and where are nonsense mRNAs degraded in mammalian cells?''; PubMedEurope PMCScholia
Singh G, Rebbapragada I, Lykke-Andersen J.; ''A competition between stimulators and antagonists of Upf complex recruitment governs human nonsense-mediated mRNA decay.''; PubMedEurope PMCScholia
Kashima I, Yamashita A, Izumi N, Kataoka N, Morishita R, Hoshino S, Ohno M, Dreyfuss G, Ohno S.; ''Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay.''; PubMedEurope PMCScholia
Clerici M, Mourão A, Gutsche I, Gehring NH, Hentze MW, Kulozik A, Kadlec J, Sattler M, Cusack S.; ''Unusual bipartite mode of interaction between the nonsense-mediated decay factors, UPF1 and UPF2.''; PubMedEurope PMCScholia
Kashima I, Jonas S, Jayachandran U, Buchwald G, Conti E, Lupas AN, Izaurralde E.; ''SMG6 interacts with the exon junction complex via two conserved EJC-binding motifs (EBMs) required for nonsense-mediated mRNA decay.''; PubMedEurope PMCScholia
Lejeune F, Li X, Maquat LE.; ''Nonsense-mediated mRNA decay in mammalian cells involves decapping, deadenylating, and exonucleolytic activities.''; PubMedEurope PMCScholia
Neu-Yilik G, Kulozik AE.; ''NMD: multitasking between mRNA surveillance and modulation of gene expression.''; PubMedEurope PMCScholia
Ishigaki Y, Li X, Serin G, Maquat LE.; ''Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20.''; PubMedEurope PMCScholia
Durand S, Cougot N, Mahuteau-Betzer F, Nguyen CH, Grierson DS, Bertrand E, Tazi J, Lejeune F.; ''Inhibition of nonsense-mediated mRNA decay (NMD) by a new chemical molecule reveals the dynamic of NMD factors in P-bodies.''; PubMedEurope PMCScholia
Gehring NH, Neu-Yilik G, Schell T, Hentze MW, Kulozik AE.; ''Y14 and hUpf3b form an NMD-activating complex.''; PubMedEurope PMCScholia
Chamieh H, Ballut L, Bonneau F, Le Hir H.; ''NMD factors UPF2 and UPF3 bridge UPF1 to the exon junction complex and stimulate its RNA helicase activity.''; PubMedEurope PMCScholia
Isken O, Kim YK, Hosoda N, Mayeur GL, Hershey JW, Maquat LE.; ''Upf1 phosphorylation triggers translational repression during nonsense-mediated mRNA decay.''; PubMedEurope PMCScholia
Lykke-Andersen J.; ''Identification of a human decapping complex associated with hUpf proteins in nonsense-mediated decay.''; PubMedEurope PMCScholia
Franks TM, Singh G, Lykke-Andersen J.; ''Upf1 ATPase-dependent mRNP disassembly is required for completion of nonsense- mediated mRNA decay.''; PubMedEurope PMCScholia
Unterholzner L, Izaurralde E.; ''SMG7 acts as a molecular link between mRNA surveillance and mRNA decay.''; PubMedEurope PMCScholia
Chiu SY, Serin G, Ohara O, Maquat LE.; ''Characterization of human Smg5/7a: a protein with similarities to Caenorhabditis elegans SMG5 and SMG7 that functions in the dephosphorylation of Upf1.''; PubMedEurope PMCScholia
Shibuya T, Tange TØ, Sonenberg N, Moore MJ.; ''eIF4AIII binds spliced mRNA in the exon junction complex and is essential for nonsense-mediated decay.''; PubMedEurope PMCScholia
Hwang J, Sato H, Tang Y, Matsuda D, Maquat LE.; ''UPF1 association with the cap-binding protein, CBP80, promotes nonsense-mediated mRNA decay at two distinct steps.''; PubMedEurope PMCScholia
Silva AL, Ribeiro P, Inácio A, Liebhaber SA, Romão L.; ''Proximity of the poly(A)-binding protein to a premature termination codon inhibits mammalian nonsense-mediated mRNA decay.''; PubMedEurope PMCScholia
Singh G, Jakob S, Kleedehn MG, Lykke-Andersen J.; ''Communication with the exon-junction complex and activation of nonsense-mediated decay by human Upf proteins occur in the cytoplasm.''; PubMedEurope PMCScholia
Fernández IS, Yamashita A, Arias-Palomo E, Bamba Y, Bartolomé RA, Canales MA, Teixidó J, Ohno S, Llorca O.; ''Characterization of SMG-9, an essential component of the nonsense-mediated mRNA decay SMG1C complex.''; PubMedEurope PMCScholia
Palacios IM, Gatfield D, St Johnston D, Izaurralde E.; ''An eIF4AIII-containing complex required for mRNA localization and nonsense-mediated mRNA decay.''; PubMedEurope PMCScholia
Chen CY, Shyu AB.; ''Rapid deadenylation triggered by a nonsense codon precedes decay of the RNA body in a mammalian cytoplasmic nonsense-mediated decay pathway.''; PubMedEurope PMCScholia
Chakrabarti S, Jayachandran U, Bonneau F, Fiorini F, Basquin C, Domcke S, Le Hir H, Conti E.; ''Molecular mechanisms for the RNA-dependent ATPase activity of Upf1 and its regulation by Upf2.''; PubMedEurope PMCScholia
Denning G, Jamieson L, Maquat LE, Thompson EA, Fields AP.; ''Cloning of a novel phosphatidylinositol kinase-related kinase: characterization of the human SMG-1 RNA surveillance protein.''; PubMedEurope PMCScholia
Cho H, Han S, Choe J, Park SG, Choi SS, Kim YK.; ''SMG5-PNRC2 is functionally dominant compared with SMG5-SMG7 in mammalian nonsense-mediated mRNA decay.''; PubMedEurope PMCScholia
Lai T, Cho H, Liu Z, Bowler MW, Piao S, Parker R, Kim YK, Song H.; ''Structural basis of the PNRC2-mediated link between mrna surveillance and decapping.''; PubMedEurope PMCScholia
Nicholson P, Yepiskoposyan H, Metze S, Zamudio Orozco R, Kleinschmidt N, Mühlemann O.; ''Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors.''; PubMedEurope PMCScholia
Yamashita A, Chang TC, Yamashita Y, Zhu W, Zhong Z, Chen CY, Shyu AB.; ''Concerted action of poly(A) nucleases and decapping enzyme in mammalian mRNA turnover.''; PubMedEurope PMCScholia
Ohnishi T, Yamashita A, Kashima I, Schell T, Anders KR, Grimson A, Hachiya T, Hentze MW, Anderson P, Ohno S.; ''Phosphorylation of hUPF1 induces formation of mRNA surveillance complexes containing hSMG-5 and hSMG-7.''; PubMedEurope PMCScholia
Chan WK, Huang L, Gudikote JP, Chang YF, Imam JS, MacLean JA, Wilkinson MF.; ''An alternative branch of the nonsense-mediated decay pathway.''; PubMedEurope PMCScholia
Gehring NH, Lamprinaki S, Hentze MW, Kulozik AE.; ''The hierarchy of exon-junction complex assembly by the spliceosome explains key features of mammalian nonsense-mediated mRNA decay.''; PubMedEurope PMCScholia
Bühler M, Steiner S, Mohn F, Paillusson A, Mühlemann O.; ''EJC-independent degradation of nonsense immunoglobulin-mu mRNA depends on 3' UTR length.''; PubMedEurope PMCScholia
Hosoda N, Kim YK, Lejeune F, Maquat LE.; ''CBP80 promotes interaction of Upf1 with Upf2 during nonsense-mediated mRNA decay in mammalian cells.''; PubMedEurope PMCScholia
Bhuvanagiri M, Schlitter AM, Hentze MW, Kulozik AE.; ''NMD: RNA biology meets human genetic medicine.''; PubMedEurope PMCScholia
Buchwald G, Ebert J, Basquin C, Sauliere J, Jayachandran U, Bono F, Le Hir H, Conti E.; ''Insights into the recruitment of the NMD machinery from the crystal structure of a core EJC-UPF3b complex.''; PubMedEurope PMCScholia
Yamashita A, Ohnishi T, Kashima I, Taya Y, Ohno S.; ''Human SMG-1, a novel phosphatidylinositol 3-kinase-related protein kinase, associates with components of the mRNA surveillance complex and is involved in the regulation of nonsense-mediated mRNA decay.''; PubMedEurope PMCScholia
Isken O, Maquat LE.; ''Quality control of eukaryotic mRNA: safeguarding cells from abnormal mRNA function.''; PubMedEurope PMCScholia
Yamashita A, Izumi N, Kashima I, Ohnishi T, Saari B, Katsuhata Y, Muramatsu R, Morita T, Iwamatsu A, Hachiya T, Kurata R, Hirano H, Anderson P, Ohno S.; ''SMG-8 and SMG-9, two novel subunits of the SMG-1 complex, regulate remodeling of the mRNA surveillance complex during nonsense-mediated mRNA decay.''; PubMedEurope PMCScholia
Glavan F, Behm-Ansmant I, Izaurralde E, Conti E.; ''Structures of the PIN domains of SMG6 and SMG5 reveal a nuclease within the mRNA surveillance complex.''; PubMedEurope PMCScholia
Huntzinger E, Kashima I, Fauser M, Saulière J, Izaurralde E.; ''SMG6 is the catalytic endonuclease that cleaves mRNAs containing nonsense codons in metazoan.''; PubMedEurope PMCScholia
Couttet P, Grange T.; ''Premature termination codons enhance mRNA decapping in human cells.''; PubMedEurope PMCScholia
Ivanov PV, Gehring NH, Kunz JB, Hentze MW, Kulozik AE.; ''Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways.''; PubMedEurope PMCScholia
Cho H, Kim KM, Kim YK.; ''Human proline-rich nuclear receptor coregulatory protein 2 mediates an interaction between mRNA surveillance machinery and decapping complex.''; PubMedEurope PMCScholia
Kunz JB, Neu-Yilik G, Hentze MW, Kulozik AE, Gehring NH.; ''Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA decay and translation.''; PubMedEurope PMCScholia
Behm-Ansmant I, Kashima I, Rehwinkel J, Saulière J, Wittkopp N, Izaurralde E.; ''mRNA quality control: an ancient machinery recognizes and degrades mRNAs with nonsense codons.''; PubMedEurope PMCScholia
Lykke-Andersen J, Shu MD, Steitz JA.; ''Communication of the position of exon-exon junctions to the mRNA surveillance machinery by the protein RNPS1.''; PubMedEurope PMCScholia
Eberle AB, Stalder L, Mathys H, Orozco RZ, Mühlemann O.; ''Posttranscriptional gene regulation by spatial rearrangement of the 3' untranslated region.''; PubMedEurope PMCScholia
Rebbapragada I, Lykke-Andersen J.; ''Execution of nonsense-mediated mRNA decay: what defines a substrate?''; PubMedEurope PMCScholia
Maquat LE, Gong C.; ''Gene expression networks: competing mRNA decay pathways in mammalian cells.''; PubMedEurope PMCScholia
Fukuhara N, Ebert J, Unterholzner L, Lindner D, Izaurralde E, Conti E.; ''SMG7 is a 14-3-3-like adaptor in the nonsense-mediated mRNA decay pathway.''; PubMedEurope PMCScholia
Le Hir H, Gatfield D, Izaurralde E, Moore MJ.; ''The exon-exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay.''; PubMedEurope PMCScholia
Mühlemann O, Eberle AB, Stalder L, Zamudio Orozco R.; ''Recognition and elimination of nonsense mRNA.''; PubMedEurope PMCScholia
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.
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.
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)
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).
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.
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.
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DataNodes
SMG5 SMG7 SMG6 PP2A
Translated mRNPPhosphorylated UPF1 EJC
Translated mRNPSMG8
SMG9 ComplexUPF1 EJC
Translated mRNPAnnotated Interactions
SMG5 SMG7 SMG6 PP2A
Translated mRNPA 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.
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.
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)
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.
Phosphorylated UPF1 EJC
Translated mRNPPhosphorylated UPF1 EJC
Translated mRNPSMG8
SMG9 ComplexUPF1 EJC
Translated mRNPUPF1 EJC
Translated mRNP