Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2017 Mar 19;372(1716):20160176.
doi: 10.1098/rstb.2016.0176.

Human eIF3: from 'blobology' to biological insight

Jamie H D Cate  1   2
Affiliations
Review

Human eIF3: from 'blobology' to biological insight

Jamie H D Cate. Philos Trans R Soc Lond B Biol Sci. .

Abstract

Translation in eukaryotes is highly regulated during initiation, a process impacted by numerous readouts of a cell's state. There are many cases in which cellular messenger RNAs likely do not follow the canonical 'scanning' mechanism of translation initiation, but the molecular mechanisms underlying these pathways are still being uncovered. Some RNA viruses such as the hepatitis C virus use highly structured RNA elements termed internal ribosome entry sites (IRESs) that commandeer eukaryotic translation initiation, by using specific interactions with the general eukaryotic translation initiation factor eIF3. Here, I present evidence that, in addition to its general role in translation, eIF3 in humans and likely in all multicellular eukaryotes also acts as a translational activator or repressor by binding RNA structures in the 5'-untranslated regions of specific mRNAs, analogous to the role of the mediator complex in transcription. Furthermore, eIF3 in multicellular eukaryotes also harbours a 5' 7-methylguanosine cap-binding subunit-eIF3d-which replaces the general cap-binding initiation factor eIF4E in the translation of select mRNAs. Based on results from cell biological, biochemical and structural studies of eIF3, it is likely that human translation initiation proceeds through dozens of different molecular pathways, the vast majority of which remain to be explored.This article is part of the themed issue 'Perspectives on the ribosome'.

Keywords: IRES; eIF3; eIF3d; eIF4E; mediator; translation initiation.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Early model for the mechanism of translation initiation. The nomenclature of initiation factors changed as follows [52]: eIF-1 now eIF1, eIF-2 now eIF2, eIF-3 now eIF3, eIF-4A now eIF4A, eIF-4B now eIF4B, eIF-4C now eIF1A, eIF4-D now eIF5A, eIF-5 now eIF5. Figure from [44].
Figure 2.
Figure 2.
Negative stain EM images of ‘native’ 40S subunits. (a) Examples of negatively stained particles. (b) Model of eIF3 bound to the 40S subunit, in three orientations. These 40S subunit preparations retained eIF3 bound to the platform region. From [54].
Figure 3.
Figure 3.
Structural core of human eIF3. Comparisons of negatively stained reconstructions of recombinant 12-subunit eIF3 (approx. 700 kDa), eight-subunit core of eIF3 (approx. 400 kDa), and the cryo-EM reconstruction of natively purified intact eIF3 (approx. 800 kDa). From [81].
Figure 4.
Figure 4.
Cryo-EM reconstruction of the 8-subunit core of human eIF3. The position of the eight subunits in the core of eIF3, left, were determined by N-terminal tagging and comparison with the proteasomal lid, right. From [27].
Figure 5.
Figure 5.
Roles of helix–loop–helix RNA-binding motifs in eIF3 in HCV IRES-mediated translation. The motif in subunit eIF3a mediates start codon recognition, whereas the motif in eIF3c contributes to a later step involving eIF5B. From [27].
Figure 6.
Figure 6.
Different modes of eIF3 binding to pre-initiation complexes. (a) Left: a 43S pre-initiation complex. Right: eIF3 bound to a classical swine fever virus (CSFV) IRES-40S complex. Figures adapted from [88,89]. (b) Model of the CSFV IRES interactions with subunits eIF3a and eIF3c. From [90].
Figure 7.
Figure 7.
Models of eIF3 wrapping around the entirety of the 40S ribosomal subunit. (a) Yeast 48S pre-initiation complex, viewed from the perspective of the 60S subunit interface. Adapted from [93]. (b) Model of mammalian eIF3 bound to the 40S subunit, viewed from the solvent side of the 40S subunit. Updated from [90].
Figure 8.
Figure 8.
Mechanism of 5′ m7G cap-binding by eIF3 in translation of JUN mRNA. Upon binding the specific stem–loop in the JUN 5′UTR, eIF3d binds the 5′ cap to promote translation. An RNA element near the 5′ cap prevents eIF4F activation of JUN mRNA translation. Updated from [102].
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Ramakrishnan V. 2014. The ribosome emerges from a black box. Cell 159, 979–984. (10.1016/j.cell.2014.10.052) - DOI - PubMed
    1. Glaeser RM. 2016. How good can cryo-EM become? Nat. Methods 13, 28–32. (10.1038/nmeth.3695) - DOI - PubMed
    1. Nogales E. 2016. The development of cryo-EM into a mainstream structural biology technique. Nat. Methods 13, 24–27. (10.1038/nmeth.3694) - DOI - PMC - PubMed
    1. Jackson RJ, Hellen CUT, Pestova TV. 2010. The mechanism of eukaryotic translation initiation and principles of its regulation. Nat. Rev. Mol. Cell Biol. 11, 113–127. (10.1038/nrm2838) - DOI - PMC - PubMed
    1. Hinnebusch AG. 2014. The scanning mechanism of eukaryotic translation initiation. Annu. Rev. Biochem. 83, 779–812. (10.1146/annurev-biochem-060713-035802) - DOI - PubMed

Publication types

MeSH terms

Substances

LinkOut - more resources

-