Fig. 1

Models for NMD. a In non-polarized cells, the pioneer round of translation, i.e., the translation of newly made CBC-bound mRNAs, and 3′UTR EJC-mediated NMD, can take place either on the cytoplasmic side of the nuclear envelope (shown) or after disassociating with the nuclear envelop (no shown). Generally, those 3′UTR EJC-mediated NMD targets that escape decay are remodeled to contain eIF4E at their 5′ cap, lose any remaining EJCs, and become immune to further NMD (not shown), unless they continue to undergo NMD mediated by a long and/or structured 3′UTR. While the decay of newly made CBC-bound mRNAs whose NMD is triggered by a long and/or structured 3′UTR can also occur on the cytoplasmic side of the nuclear envelope, once remodeled to eIF4E-bound mRNAs, they continue to undergo NMD, presumably in the cytosol (not shown). Note that while NMD targets are generally bound by FMRP, the FMRP-mediated block in translation is incomplete since FMRP binding is not 100% efficient. FMRP is not shown. Red pacman, NMD decay machinery; CBC, CBP80 − CBP20 at the 5′ m⁷G cap of newly made mRNAs; green balls, 80S ribosome with nascent peptide; STOP, translation termination codon; EJC, exon-junction complex. b In polarized cells, the translation of at least a fraction of newly made mRNAs appears to be inhibited until the mRNA is properly transported in granules to a distal projection. Where in the cell and when, if at all, during transport and localization the CBC is replaced by eIF4E remains to be determined. Based on work using non-polarized cells, FMRP binding to target mRNAs, including NMD targets, requires its direct interaction with PABPC1, which is bound to the poly(A) tail of the mRNA. According to this model, once localized to a distal projection, FMRP is removed from the NMD target by the dephosphorylation of FMRP, allowing translation and, as a consequence, decay by NMD. The step(s) at which translation is inhibited prior to granule localization remains to be defined