UPF1 binds an mRNP with a termination codon preceding an Exon Junction Complex

Stable Identifier
Homo sapiens
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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.

Literature References
PubMed ID Title Journal Year
18256688 Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways EMBO J 2008
11532962 The exon-exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay EMBO J 2001
11546874 Communication of the position of exon-exon junctions to the mRNA surveillance machinery by the protein RNPS1 Science 2001
16209946 Exon-junction complex components specify distinct routes of nonsense-mediated mRNA decay with differential cofactor requirements Mol Cell 2005
20479275 Insights into the recruitment of the NMD machinery from the crystal structure of a core EJC-UPF3b complex Proc Natl Acad Sci U S A 2010
19503078 A UPF3-mediated regulatory switch that maintains RNA surveillance Nat Struct Mol Biol 2009
19859661 Nonsense-mediated mRNA decay in human cells: mechanistic insights, functions beyond quality control and the double-life of NMD factors Cell Mol Life Sci 2010
18423202 Upf1 phosphorylation triggers translational repression during nonsense-mediated mRNA decay Cell 2008
21419344 Molecular mechanisms for the RNA-dependent ATPase activity of Upf1 and its regulation by Upf2 Mol Cell 2011
16186820 CBP80 promotes interaction of Upf1 with Upf2 during nonsense-mediated mRNA decay in mammalian cells Nat Struct Mol Biol 2005
19417104 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 Genes Dev 2009
19478851 The hierarchy of exon-junction complex assembly by the spliceosome explains key features of mammalian nonsense-mediated mRNA decay PLoS Biol 2009
11551508 Evidence for a pioneer round of mRNA translation: mRNAs subject to nonsense-mediated decay in mammalian cells are bound by CBP80 and CBP20 Cell 2001
18524595 The meaning of nonsense Trends Cell Biol 2008
16601204 Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA decay and translation RNA 2006
19909264 Gene expression networks: competing mRNA decay pathways in mammalian cells Biochem Soc Trans 2009
18066079 NMD factors UPF2 and UPF3 bridge UPF1 to the exon junction complex and stimulate its RNA helicase activity Nat Struct Mol Biol 2008
19359157 Execution of nonsense-mediated mRNA decay: what defines a substrate? Curr Opin Cell Biol 2009
16452507 Binding of a novel SMG-1-Upf1-eRF1-eRF3 complex (SURF) to the exon junction complex triggers Upf1 phosphorylation and nonsense-mediated mRNA decay Genes Dev 2006
14973490 An eIF4AIII-containing complex required for mRNA localization and nonsense-mediated mRNA decay Nature 2004
17363904 An alternative branch of the nonsense-mediated decay pathway EMBO J 2007
17352659 The nonsense-mediated decay RNA surveillance pathway Annu Rev Biochem 2007
20691628 UPF1 association with the cap-binding protein, CBP80, promotes nonsense-mediated mRNA decay at two distinct steps Mol Cell 2010
12718880 Y14 and hUpf3b form an NMD-activating complex Mol Cell 2003
18657639 Recognition and elimination of nonsense mRNA Biochim Biophys Acta 2008
19556969 Unusual bipartite mode of interaction between the nonsense-mediated decay factors, UPF1 and UPF2 EMBO J 2009
15034551 eIF4AIII binds spliced mRNA in the exon junction complex and is essential for nonsense-mediated decay Nat Struct Mol Biol 2004
17803942 Communication with the exon-junction complex and activation of nonsense-mediated decay by human Upf proteins occur in the cytoplasm Mol Cell 2007
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