eIF4E: New Family Members, New Binding Partners, New Roles

Abstract

Eukaryotic initiation factor 4E (eIF4E) has long been known as the cap-binding protein that participates in recruitment of mRNA to the ribosome. A number of recent advances have not only increased our understanding of how eIF4E acts in translation but also uncovered non-translational roles. New structures have been determined for eIF4E in complex with various ligands and for other cap-binding proteins. We have also learned that most eukaryotic organisms express multiple eIF4E family members, some involved in general translation but others having specialized functions, including repression of translation. A number of new eIF4E-binding proteins have been reported, some of which tether it to specific mRNAs.The 7-methylguanosine-containing "cap" plays an essential role at each stage of the mRNA "life cycle": transcription, splicing, nuclear export, translation, translational repression, and degradation. This is mediated by specific cap-binding proteins, of which at least 10 have been discovered so far (supplemental Table S1). The most widely studied and best understood of these cap-binding proteins is eIF4E.2 eIF4E was discovered as a protein that promotes translation initiation, and most of the work on its structure, function, and regulation has been performed with this role in mind. As a canonical initiation factor involved in recruitment of mRNA to the ribosome, eIF4E has the potential to influence expression of virtually every protein in the cell. It is against this backdrop of eIF4E serving as a translational enhancer that discoveries over the past decade have been so surprising, that eIF4E can also function as a translational repressor. Another unexpected result of recent research is that nearly all eukaryotes express multiple eIF4E family members and that they can have different functions in the cell. A third research trend has been the discovery of new eIF4E-binding partners, some of which tether eIF4E to specific mRNAs. This minireview touches on all of these new directions in eIF4E research. Role of eIF4E in TranslationRecruitment of mRNA to the 43 S initiation complex to form the 48 S initiation complex requires eIF3, the poly(A)-binding protein, and the eIF4 proteins (Fig. 1B) (1). The eIF4 factors consist of eIF4A, a 46-kDa RNA helicase; eIF4B, a 70-kDa RNA-binding and RNA-annealing protein; eIF4E, a 25-kDa cap-binding protein; eIF4H, a 25-kDa protein that acts with eIF4B to stimulate eIF4A helicase activity; and eIF4G, a 185-kDa protein that co-localizes all of the other proteins involved in mRNA recruitment on the 40 S subunit.3 At least four cis-acting elements affect the efficiency of mRNA translation: the cap, the poly(A) tail, sequence elements in the 5Ј-UTR, and sequence elements in the 3Ј-UTR. It is well established that eIF4E stimulates translation of capped mRNAs, but mRNAs differ in their dependence on eIF4E. For instance, mRNAs with extensive 5Ј-UTR secondary structure have a greater requirement for the eIF4A-based unwinding machinery recruited by eIF4E (Fig. 1B) (2).The tertiary structures ...

Human cytomegalovirus UL69 protein facilitates translation by associating with the mRNA cap-binding complex and excluding 4EBP1

“…A two-hybrid screen identified eIF4A1 and PABPC1 as putative partners that are directly contacted by the viral protein (Table 1). eIF4A1 is a constituent of the eIF4F cap-binding complex and PABPC1 binds directly to the complex (26). These predicted interactions were confirmed by coimmunoprecipitation analyses (Fig.…”

Two Arabidopsis Loci Encode Novel Eukaryotic Initiation Factor 4E Isoforms That Are Functionally Distinct from the Conserved Plant Eukaryotic Initiation Factor 4E

“…However, due to their low binding affinity for eIF4G relative to eIF4E and their low level of expression, it seems unlikely that these genes contribute substantially to translation initiation in most plant tissues. Increasing numbers of noncanonical eIF4E family members have been described in eukaryotes (Rhoads, 2009). As more plant genomes are sequenced, other events similar to the EIF4E duplication and divergence in Brassicaceae may be observed.…”

“…In some organisms, however, secondary Class I isoforms exist with expression patterns and functions divergent from the conserved eIF4E (Rhoads, 2009). Caenorhabditis elegans has four isoforms involved in differentiation between mono-and trimethylated mRNA caps (Keiper et al, 2000) and have specialized roles for regulation of certain sets of mRNAs, particularly in the germline (Amiri et al, 2001;Song et al, 2010).…”

Resistance to discodermolide, a microtubule-stabilizing agent and senescence inducer, is 4E-BP1–dependent

“…Upon mTORC1 activation, 4E-BP1 is phosphorylated on Thr37 and Thr46, whereby it becomes primed for subsequent phosphorylation at Ser65 and Thr70 (15). Hyperphosphorylation of 4E-BP1 causes it to dissociate from eIF4E and results in enhanced translation initiation of defined subsets of mRNA (16). Conversely, mTORC1 inhibition by rapamycin leads to sequestration of eIF4E by 4E-BP1 and to decreased translation efficiency.…”