Shown is a CBP80-CBP20 (CBC)-bound mRNP from the pioneer round of translation and an eIF4E-bound mRNP from steady-state translation. CBC-bound mRNAs direct pioneer rounds of translation, whereas eIF4E-bound mRNAs, which derive from the remodeling of CBC-bound mRNAs, support the bulk of cellular protein synthesis. CBC-bound mRNAs are associated with at least one exon-junction complex (EJC) (provided they are the product of pre-mRNA splicing) and the poly(A) binding proteins PABPN1 and PABPC1. PYM, which interacts with EJC components and the small 40S ribosomal subunit (not shown), and SKAR (S6 kinase 1 ALY-REF-like target), a component of EJCs, may help to activate the pioneer round of translation. eIF3e, a non-core subunit of the eukaryotic translation initiation factor eIF3, may regulate the translation of a specific set of CBC-bound mRNAs. CTIF (CBP80-CBP20-dependent translation initiation factor) interacts directly with CBP80, as does eIF4G. It is currently unclear whether CTIF is the sole eIF4G-like molecule or if eIF4G also functions during pioneer rounds. eIF4G has been proposed to form a complex with poly(A)-bound PABPC1 to circularize and promote the translation of CBC-bound mRNAs, similar to how poly(A)-bound PABPC1 circularizes and promotes the translation of eIF4E-bound mRNAs. Importin (IMP)-β binds to IMP-α (which is a stable constituent of cap-bound CBC) and augments the translation-independent replacement of CBC by eIF4E. In contrast, the pioneer round of translation promotes the removal of EJCs and of associated RNA-binding proteins such as SF2/ASF (which also activates the pioneer round; not shown), and the replacement of PABPN1 by PABPC1. The insets depict how the SURF complex (comprising the PIK-related protein kinase SMG1, UPF1, eRF1 and eRF3) assembles together with an 80S stalled ribosome at a premature termination codon of CBC-bound mRNA. SMG1 subsequently phosphorylates UPF1 upon UPF1 and SMG1 binding to a downstream EJC during the process of nonsense-mediated mRNA decay. AUG, translation initiation codon; STOP, normal termination codon.

Shown are the signaling pathways that regulate the pioneer round of translation (top) and subsequent steady-state translation (bottom). Under conditions that activate the mTOR signaling pathway, mTORC1 becomes activated and may bind to the translation initiation factor eIF3 associated with CBP80-CBP20 (CBC)-bound mRNA resulting in the phosphorylation and dissociation of activated S6 kinase 1 (S6K1). The EJC component SKAR (S6 kinase 1 ALY-REF-like target) then recruits phosphorylated (i.e., activated) S6K1. Activated S6K1 next mediates the phosphorylation of SKAR and other downstream effectors, including possibly eIF4B and PDCD4 (programmed cell death factor 4), that also associate with CBC-bound mRNA and thereby promote the pioneer round of translation for spliced mRNAs. The Cdc42-dependent phosphorylation of S6K1 also may promote the binding of CBC to cap structures, which would further stimulate the pioneer round. Another CBC-bound mRNA constituent, SF2/ASF, binds to the RNA export receptor TAP and also triggers S6K1 signaling via mTORC1 in ways that promote CBC-bound mRNA translation. Moreover, PYM interacts with the EJC core proteins Y14-MAGOH and with the 40S ribosomal subunit to somehow promote translation of spliced mRNAs presumably during and certainly beyond the pioneer round. (Left) The boxes summarize the translational regulation of CBC-bound or eIF4E-bound mRNAs under various cell-growth conditions. Under conditions of heat shock, hypoxia or serum starvation, the pioneer round of translation is favored over steady-state translation; steady-state translation is largely inhibited by phosphorylation of eIF2α (not shown) or by binding of 4E-BP1 to eIF4E.