EIF4G

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(eukaryotic translation initiation factor 4 gamma) is a protein involved in bringing mRNA to the ribosome for translation, in general based on mRNA's distinctive guanosine cap. Species versions of eIF4G have been studied in everything from humans, to yeast, to wheat. However, eIF4G is exclusively found in domain Eukarya, not in domains Bacteria or Archaea (these do not have capped mRNA). As such be aware that when eIF4G is spoken of in this article, the statements will apply to many variants but may not hold for all, and when comparing among species comparisons are relative to human eIF4G 1.

In all species, eIF4G strongly associates with the protein that directly binds the mRNA cap: eIF4E. These two together are known as the complex eIF4F (in general, also in association with the mRNA unwinding protein eIF4A).

Within the cell eIF4G is found primarily in the cytoplasm, usually bound to eIF4E; however, it is also found in the nucleus where its function is unknown. Though in the nucleus it has been found to associate with the splicing complex, it does not appear to be involved directly in RNA splicing. It also appears to have a role in nonsense-mediated decay.

History

eIF4G stands for eukaryotic initiation factor 4 gamma (typically gamma is now replaced by G in the literature). Named so because it was initially isolated by fractionation (collecting small portions of fluid that had been separated on a column), it happened to be contained in fraction 4 gamma, and was involved in eukaryotic translation initiation.

eIF4G Binding Partners

eIF4G has been found to associate with myriad other proteins: eIF4E, MNK-1, eIF4A, CBP80, CBP20, PABP, and eIF3. eIF4G also directly binds mRNA and has multiple positively charged regions for this function (note: RNA is negatively charged, so RNA binding regions are usually very positively charged). Various IRESs also bind eIF4G directly, as do BTE CITEs.

Some RNAs that do not have caps (such as those containing IRESs) bind eIF4G specifically (in preference to other RNA-binding proteins).

eIF4G in Translation Initiation

eIF4G essentially serves the function of bringing mRNA to the 40S ribosome.

In essence, there are 3 ways that the 40S ribosome can come to recognize the start codon: scanning, internal entry, and shunting. Scanning is where the 40S ribosome slides along the RNA until recognizing a start site (typically an AUG sequence in "good context"). Internal entry is where the 40S ribosome does not start from the beginning (5' end) of the mRNA but instead starts from somewhere in the middle. Shunting is where after the 40S ribosome starts sliding along the mRNA it "jumps" or skips large sections; the mechanism for this is still unclear. eIF4G is required for all these types of initiation (with the exception of internal initiation by HCV or Cripavirus IRES initiation).

eIF4G in Disease

eIF4G has been implicated in breast cancer. It appears in increased levels in certain types of breast cancer (and others) and increases IRES containing mRNA production; these mRNAs produce hypoxia and stress related proteins that encourage blood vessel invasion (which is important for cancer cells—requiring large amounts of nutrients to divide quickly and form sizable tumors).

Role in Aging

Regulation of tranlsation initiation by eIF4G is vital for protein synthesis in developing organisms, for example yeast and nematodes. Complete removal of eIF4G is lethal in yeast.[1] In the round worm, C. elegans, knockout of eIF4G leads to animals that cannot develop past the early larval stage (L2) of development.[2] The critical role of eIF4G in development appears to be reversed in adulthood, when eIF4G dysregulation negatively impacts lifespan and increases susceptibility to certain aging-related diseases (see eIF4G in diseases above). Inhibiting eIF4G during adulthood in C. elegans drastically extends lifespan, comparable to the lifespan increase exhibited during dietary restriction.[3] In addition, inhibiting eIF4G reduces overall protein translation, while preferentially translating mRNA of genes important for responding to stress and against those associated with growth and reproduction.[4] Thus eIF4G appears to control differential mRNA translation during periods or growth and stress, which may ultimately lead to age related decline.

Importance in Virology

As previously mentioned, eIF4G is bound by IRESs, which were initially discovered in viruses. Some viral IRESs directly bind eIF4G, and co-opt it for gaining access to the ribosome. Some cellular RNAs also contain IRESs (including eIF4G itself).[5]

Some viruses do this by cutting off part of eIF4G such that eIF4E no longer binds it. This has the effect of preventing most cellular mRNAs from binding eIF4G (which require eIF4E to ride along on eIF4G); however, the few cellular mRNAs with IRESs still translate under these conditions.

Binding sites for viral IRES's: EMCV IRES aa 746-949.[6]

References

  1. ↑ Goyer C, Altmann M, Lee HS, Blanc A, Deshmukh M, Woolford JL Jr, Trachsel H, Sonenberg N (1993). "TIF4631 and TIF4632: two yeast genes encoding the high-molecular-weight subunits of the cap-binding protein complex (eukaryotic initiation factor 4F) contain an RNA recognition motif-like sequence and carry out an essential function". MOLECULAR AND CELLULAR BIOLOGY 13 (8): 4860–4874. doi:10.1128/MCB.13.8.4860. PMID 8336723. 
  2. ↑ Contreras V, Richardson MA, Hao E, Keiper BD (2008). "Depletion of the cap-associated isoform of translation factor eIF4G induces germline apoptosis in C. elegans". Cell Death and Differentiation 15: 1232–1242. doi:10.1038/cdd.2008.46. PMID 18451872. 
  3. ↑ Kally Z. Pan, Julia E. Palter, Aric N. Rogers, Anders Olsen, Di Chen, Gordon J. Lithgow, Pankaj Kapahi (2007). "Inhibition of mRNA translation extends lifespan in Caenorhabditis elegans". Aging Cell 6 (1): 111–119. doi:10.1111/j.1474-9726.2006.00266.x. PMID 17266680. 
  4. ↑ Rogers AN, Chen D, McColl G, Czerwieniec G, Felkey K, Gibson BW, Hubbard A, Melov S, Lithgow GJ, Kapahi P (2011). "Life span extension via eIF4G inhibition is mediated by posttranscriptional remodeling of stress response gene expression in C. elegans". Cell Metabolism 14 (1): 55–66. doi:10.1016/j.cmet.2011.05.010. PMID 21723504. 
  5. ↑ Weiniu Gan, Michael La Celle, and Robert E. Rhoads (1998). "Functional Characterization of the Internal Ribosome Entry Site of eIF4G mRNA*". The Journal of Biological Chemistry 273 (9): 5006–5012. doi:10.1074/jbc.273.9.5006. PMID 9478948. 
  6. ↑ Ivan B. Lomakin,1 Christopher U. T. Hellen,1 and Tatyana V. Pestova (2000). "Physical Association of Eukaryotic Initiation Factor 4G (eIF4G) with eIF4A Strongly Enhances Binding of eIF4G to the Internal Ribosomal Entry Site of Encephalomyocarditis Virus and Is Required for Internal Initiation of Translation". Mol Cell Biol 20 (16): 6019–6029. doi:10.1128/MCB.20.16.6019-6029.2000. PMC 86078. PMID 10913184. 
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