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

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

Stable Identifier

R-HSA-927832

Type

Reaction [binding]

Species

Homo sapiens

Compartment

cytosol

ReviewStatus

5/5

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

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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
11532962	The exon-exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay Le Hir, H, Moore, MJ, Gatfield, D, Izaurralde, E	EMBO J	2001
18256688	Interactions between UPF1, eRFs, PABP and the exon junction complex suggest an integrated model for mammalian NMD pathways Ivanov, PV, Gehring, NH, Kunz, JB, Kulozik, AE, Hentze, MW	EMBO J	2008
11546874	Communication of the position of exon-exon junctions to the mRNA surveillance machinery by the protein RNPS1 Shu, MD, Steitz, JA, Lykke-Andersen, J	Science	2001
16209946	Exon-junction complex components specify distinct routes of nonsense-mediated mRNA decay with differential cofactor requirements Gehring, NH, Neu-Yilik, G, Kunz, JB, Kulozik, AE, Viegas, MH, Breit, S, Hentze, MW	Mol Cell	2005
20479275	Insights into the recruitment of the NMD machinery from the crystal structure of a core EJC-UPF3b complex Sauliere, J, Ebert, J, Bono, F, Buchwald, G, Conti, E, Le Hir, H, Basquin, C, Jayachandran, U	Proc Natl Acad Sci U S A	2010
19503078	A UPF3-mediated regulatory switch that maintains RNA surveillance Gécz, J, Wilkinson, MF, Nguyen, LS, Le Hir, H, Bhalla, AD, Chan, WK, Huang, L	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 Yepiskoposyan, H, Kleinschmidt, N, Zamudio Orozco, R, Metze, S, Muhlemann, O, Nicholson, P	Cell Mol Life Sci	2010
18423202	Upf1 phosphorylation triggers translational repression during nonsense-mediated mRNA decay Isken, O, Kim, YK, Maquat, LE, Mayeur, GL, Hershey, JW, Hosoda, N	Cell	2008
21419344	Molecular mechanisms for the RNA-dependent ATPase activity of Upf1 and its regulation by Upf2 Domcke, S, Chakrabarti, S, Conti, E, Le Hir, H, Basquin, C, Fiorini, F, Jayachandran, U, Bonneau, F	Mol Cell	2011
16186820	CBP80 promotes interaction of Upf1 with Upf2 during nonsense-mediated mRNA decay in mammalian cells Kim, YK, Maquat, LE, Lejeune, F, Hosoda, N	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 Ohno, S, Katsuhata, Y, Yamashita, A, Ohnishi, T, Iwamatsu, A, Anderson, P, Izumi, N, Kurata, R, Hirano, H, Muramatsu, R, Morita, T, Saari, B, Hachiya, T, Kashima, I	Genes Dev	2009
19478851	The hierarchy of exon-junction complex assembly by the spliceosome explains key features of mammalian nonsense-mediated mRNA decay Gehring, NH, Lamprinaki, S, Kulozik, AE, Hentze, MW	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 Serin, G, Li, X, Maquat, LE, Ishigaki, Y	Cell	2001
18524595	The meaning of nonsense Stalder, L, Muhlemann, O	Trends Cell Biol	2008
16601204	Functions of hUpf3a and hUpf3b in nonsense-mediated mRNA decay and translation Gehring, NH, Neu-Yilik, G, Kunz, JB, Kulozik, AE, Hentze, MW	RNA	2006
19909264	Gene expression networks: competing mRNA decay pathways in mammalian cells Gong, C, Maquat, LE	Biochem Soc Trans	2009
18066079	NMD factors UPF2 and UPF3 bridge UPF1 to the exon junction complex and stimulate its RNA helicase activity Le Hir, H, Ballut, L, Bonneau, F, Chamieh, H	Nat Struct Mol Biol	2008
19359157	Execution of nonsense-mediated mRNA decay: what defines a substrate? Rebbapragada, I, Lykke-Andersen, J	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 Kataoka, N, Dreyfuss, G, Ohno, S, Hoshino, S, Morishita, R, Yamashita, A, Ohno, M, Izumi, N, Kashima, I	Genes Dev	2006
14973490	An eIF4AIII-containing complex required for mRNA localization and nonsense-mediated mRNA decay Palacios, IM, St Johnston, D, Gatfield, D, Izaurralde, E	Nature	2004
17363904	An alternative branch of the nonsense-mediated decay pathway Wilkinson, MF, Chan, WK, Imam, JS, Huang, L, Chang, YF, Gudikote, JP, MacLean JA, 2nd	EMBO J	2007
17352659	The nonsense-mediated decay RNA surveillance pathway Wilkinson, MF, Imam, JS, Chang, YF	Annu Rev Biochem	2007
20691628	UPF1 association with the cap-binding protein, CBP80, promotes nonsense-mediated mRNA decay at two distinct steps Sato, H, Maquat, LE, Matsuda, D, Tang, Y, Hwang, J	Mol Cell	2010
12718880	Y14 and hUpf3b form an NMD-activating complex Gehring, NH, Neu-Yilik, G, Kulozik, AE, Hentze, MW, Schell, T	Mol Cell	2003
18657639	Recognition and elimination of nonsense mRNA Stalder, L, Eberle, AB, Zamudio Orozco, R, Muhlemann, O	Biochim Biophys Acta	2008
19556969	Unusual bipartite mode of interaction between the nonsense-mediated decay factors, UPF1 and UPF2 Mourão, A, Gehring, NH, Clerici, M, Cusack, S, Sattler, M, Gutsche, I, Hentze, MW, Kadlec, J, Kulozik, A	EMBO J	2009
15034551	eIF4AIII binds spliced mRNA in the exon junction complex and is essential for nonsense-mediated decay Shibuya, T, Moore, MJ, Tange, TØ, Sonenberg, N	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 Kleedehn, MG, Jakob, S, Singh, G, Lykke-Andersen, J	Mol Cell	2007