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Evolutionarily conserved developmental pathways
Translation initiation is mediated by the binding of a pre-initiation complex to the 5' cap of the mRNA (reviewed in (Merrick, 1996 ; Gingras, 1999) that in turn recruits the small subunit of the 40S ribosome to the mRNA. The pre-initiation complex consists of the cap binding protein, eIF4E, and a scaffolding protein, eIF4G, which mediates interactions with various components of the 40S initiation complex. In many organisms there is also a third protein in the complex, eIF4A, an ATP dependent RNA helicase. Modulating eIF4E activity appears to be a key control point for regulating translation. One of the most common mechanisms of regulation is by controlling the association eIF4E with eIF4G. Factors such as poly-A binding protein that promote the association between eIF4E and eIF4G activate translation initiation, while factors such as the 4E-binding proteins (4E-BPs; see Drosphila 4E-BP) that block their association, inhibit initiation (Graham, 2011 and references therein).
In many circumstances, translation initiation is the rate-limiting step, and it is often the target of regulation. Translation initiation begins with the binding of the 43S preinitiation complex to the mRNA. In the cap-dependent mode of translation initiation, the m7GpppN (N, any nucleotide) cap structure (see mRNA capping at Genome Knowledge Base) at the 5' end of the mRNA attracts the eukaryotic initiation factor (eIF)4F complex to the mRNA (see Cap-dependent Translation Initiation at Genome Knowledge Base). This complex contains the cap binding protein eIF4E and the scaffold-like protein eIF4G. The cap-bound eIF4F directs the 43S complex to the 5' end of the mRNA through the interaction of eIF4G with eIF3, a multisubunit component of the 43S complex. Thus, the eIF4E-eIF4G interaction is crucial for cap-dependent translation initiation. The eIF4E binding proteins (4E-BPs) are well-characterized proteins that regulate translation initiation by blocking the eIF4E-eIF4G interaction in a reversible, growth signal-dependent manner (Gingras, 1999). 4E-BPs contain the conserved eIF4E binding sequence defined by YxxxxLphi (where x is any residue and phi is a hydrophobic residue), and compete with eIF4G to bind to the same region of eIF4E (Gingras, 1999; Marcotrigiano, 1999). 4E-BPs, however, do not discriminate among mRNAs but regulate global translation efficiency in response to external signals (Nakamura, 2004 and references therein).
Translational control is often mediated through proteins that bind to the 3' UTR of mRNA. In Drosophila oogenesis, translational repression of oskar1 (osk) RNA during its localization to the posterior pole of the oocyte is essential for embryonic patterning and germ cell formation. This repression is mediated by the osk 3' UTR binding protein Bruno (Bru), but the underlying mechanism has remained elusive. An ovarian protein, Cup, is was shown in this study to be required to repress precocious osk translation. Cup binds the 5'-cap binding translation initiation factor eIF4E through a sequence conserved among eIF4E binding proteins. A mutant Cup protein lacking this sequence fails to repress osk translation in vivo. Furthermore, Cup interacts with Bru in a yeast two-hybrid assay, and the Cup-eIF4E complex associates with Bru in an RNA-independent manner. These results suggest that translational repression of osk RNA is achieved through a 5'/3' interaction mediated by an eIF4E-Cup-Bru complex (Nakamura, 2004).
Gingras, A. C., Raught, B. and Sonenberg, N. (1999). eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation. Annu. Rev. Biochem. 68: 913-963. 10872469
Graham, P. L., Yanowitz, J. L., Penn, J. K., Deshpande, G. and Schedl, P. (2011). The translation initiation factor eIF4E regulates the sex-specific expression of the master switch gene Sxl in Drosophila melanogaster. PLoS Genet. 7(7): e1002185. PubMed Citation: 21829374
Merrick, W. C. and Hershey, J. W. B. (1996). Translational Control. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory.
Nakamura, A., Sato, K. and Hanyu-Nakamura, K. (2004). Drosophila Cup is an eIF4E binding protein that associates with Bruno and regulates oskar mRNA translation in oogenesis. Dev. Cell 6: 69-78. 14723848
date revised: 10 February 2012
Developmental Pathways conserved in Evolution
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