NMD: a multifaceted response to premature translational termination - PubMed

Figure 2. Activation of metazoan NMD by EJC-dependent interactions

The exon-junction complex (EJC) is a group of proteins deposited on an mRNA during splicing, 20-24 nt 5’ of an exon-exon boundary^,,,. The composition of the EJC is dynamic, and includes at least the core proteins Y14, Magoh, Barentz, and eIF4AIII, and one effector of NMD, Upf3^,,,-. In mammalian cells, Upf3 is loaded onto mRNAs during splicing and binds to a composite site comprised of parts of Y14, Magoh, and eIF4AIII. Upf2 is thought to join the complex in the cytoplasm via Upf3 binding, after mRNA export from the nucleus (top image). In parallel, Upf1 associates with eRF1-bound eRF3, and Smg-1, Smg-8, and Smg-9 associate with Upf1, collectively forming the SURF complex^,. If premature translational termination leads to retention of the downstream EJC then Upf1:Upf2 interaction is facilitated, leading to the formation of the DECID complex and to Upf1 phosphorylation and ATPase activation (middle image). Activation of NMD independently of Upf2, Upf3, or some EJC components has been described, suggesting that alternative pathways may also exist^,. Upf1 phosphorylation inhibits translation in cis and promotes its interaction with Smg-6, an endonuclease that can cleave the mRNA, and with the Smg-5:Smg-7 complex, which appears to promote deadenylation and decapping (bottom image)^,,,,,,. Mago=Magoh; BTZ=Barentz; R1=eRF1; R3=eRF3. Modified with permission from