Mammalian pioneer translation initiation complex and mRNA decay

Abstract

Nonsense‐mediated mRNA decay (NMD) is an mRNA surveillance pathway that largely functions to control the quality of gene expression. NMD in mammalian cells generally occurs when translation terminates sufficiently upstream of a splicing generated exon‐exon junction during a pioneer round of translation. The pioneer round utilizes newly synthesized mRNA that is bound by the cap binding protein (CBP) heterodimer CBP80‐CBP20 and, if the mRNA is a product of pre‐mRNA splicing, one or more exon junction complexes (EJCs). Ultimately, the pioneer translation initiation complex is remodeled so that CBP80‐CBP20 is replaced by eukaryotic translation initiation factor (eIF)4E and the EJCs are lost. The eIF4E‐bound translation initiation complex is not detectably targeted for NMD.We will present characterizations of the pioneer translation initiation complex. For example, CBP80 promotes NMD by interacting directly with the Upf1 NMD factor and increasing the interaction between Upf1 and Upf21. We will also discuss mRNP rearrangements that occur when translation terminates in a way that elicits NMD. Comparisons of NMD to Staufen1‐mediated mRNA decay (SMD)2 will also be made. Unlike NMD, SMD functions to conditionally decrease the expression of genes encoding mRNAs that bind Staufen1 downstream of a termination codon3. Considering that the majority of cellular mRNA is bound by eIF4E and only a small fraction is bound by CBP80‐CBP20, our finding that SMD targets mRNA undergoing pioneer and subsequent rounds of translation makes sense1.