Journal
NUCLEIC ACIDS RESEARCH
Volume 42, Issue 4, Pages 2673-2686Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkt1197
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Funding
- European Molecular Biology Laboratory EIPOD post-doctoral programme
- European Research Council [ERC] [281331]
- Swiss National Science Foundation [CRSII3_136254]
- International Graduate School in Development Health and Disease IGSDHD
- Deutsche Forschungsgemeinschaft [SFB635]
- EMBL
- Swiss National Science Foundation (SNF) [CRSII3_136254] Funding Source: Swiss National Science Foundation (SNF)
- European Research Council (ERC) [281331] Funding Source: European Research Council (ERC)
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Nonsense-mediated decay (NMD) is a eukaryotic quality control pathway, involving conserved proteins UPF1, UPF2 and UPF3b, which detects and degrades mRNAs with premature stop codons. Human UPF2 comprises three tandem MIF4G domains and a C-terminal UPF1 binding region. MIF4G-3 binds UPF3b, but the specific functions of MIF4G-1 and MIF4G-2 are unknown. Crystal structures show that both MIF4G-1 and MIF4G-2 contain N-terminal capping helices essential for stabilization of the 10-helix MIF4G core and that MIF4G-2 interacts with MIF4G-3, forming a rigid assembly. The UPF2/UPF3b/SMG1 complex is thought to activate the kinase SMG1 to phosphorylate UPF1 in vivo. We identify MIF4G-3 as the binding site and in vitro substrate of SMG1 kinase and show that a ternary UPF2 MIF4G-3/UPF3b/SMG1 complex can form in vitro. Whereas in vivo complementation assays show that MIF4G-1 and MIF4G-2 are essential for NMD, tethering assays reveal that UPF2 truncated to only MIF4G-3 and the UPF1-binding region can still partially accomplish NMD. Thus UPF2 MIF4G-1 and MIF4G-2 appear to have a crucial scaffolding role, while MIF4G-3 is the key module required for triggering NMD.
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