Disease relevance of EIF4G1

• Paip2 preferentially inhibits translation of a poly(A)-containing mRNA, but has no effect on the translation of hepatitis C virus mRNA, which is cap- and eIF4G-independent [1].
• In vivo, 100k protein displaces Mnk1 from eIF4G during adenovirus infection, or in transfected cells [2].
• Poliovirus infection engenders the cleavage of the eIF4G (formerly p220) component of eIF4F and renders this complex inactive for cap-dependent translation [3].
• In contrast, EMCV infection does not result in eIF4G cleavage [3].
• A 49-amino-acid region of eIF-4 gamma, located in the N-terminal side of the site of cleavage by Picornaviridae protease 2A, was found to be sufficient for interacting with eIF-4E [4].

High impact information on EIF4G1

• eIF4 initiation factors: effectors of mRNA recruitment to ribosomes and regulators of translation [5].
• Assembly of the eIF4E/eIF4G complex has a central role in the regulation of gene expression at the level of translation initiation [6].
• While 4EGI-1 displaces eIF4G from eIF4E, it effectively enhances 4E-BP1 association both in vitro and in cells [6].
• NSP3 binds to viral mRNA 3' consensus sequences and circularizes the mRNA via interactions with eIF4G [7].
• Here, we describe a new human PABP-interacting protein, PAIP-I, whose sequence is similar to the central portion of eIF4G and which interacts with eIF4A [8].

Chemical compound and disease context of EIF4G1

• In this paper, we show that when cells are infected with poliovirus in the presence of guanidine or 3-methylquercetin, both inhibitors of poliovirus replication, complete cleavage of p220 occurs by 3.5 h postinfection [9].
• In conclusion, monensin and nigericin are potent inhibitors of poliovirus genome replication that prevent the shutoff of host translation by poliovirus while still permitting cleavage of p220 [10].
• Monensin and nigericin prevent the inhibition of host translation by poliovirus, without affecting p220 cleavage [10].
• To obtain p220 cleavage in the absence of any other poliovirus gene products, hybrid proteins containing Pseudomonas aeruginosa exotoxin A and poliovirus protease 2Apro have been constructed [11].
• The aphthovirus Leader (173-201 amino acids) is an autocatalytic papain-like protease that cleaves translation factor eIF-4G to shut off cap-dependent host protein synthesis during infection [12].

Biological context of EIF4G1

• This effect is mediated by a bridging complex, composed of the poly(A) binding protein (PABP), eIF4G, and the cap binding protein, eIF4E [1].
• Moreover, the phosphorylation of an eIF4E mutant lacking eIF4G-binding capability is severely impaired in cells [13].
• A newly identified N-terminal amino acid sequence of human eIF4G binds poly(A)-binding protein and functions in poly(A)-dependent translation [14].
• Unlike Mnk1, for which binding to eIF4G is RNA dependent, competitive binding by 100K protein is RNA independent [15].
• The data suggest a direct or indirect interaction between the functional domains of eIF4G and cellular structures involved in cytokinesis [16].

Anatomical context of EIF4G1

• Tethering of eIF4G to adenoviral mRNAs by viral 100k protein drives ribosome shunting [17].
• While eIF4G stably associates with spliceosomes in vitro and shows close association with spliceosomal snRNPs and splicing factors in vivo, depletion studies show that it does not participate directly in the splicing reaction [18].
• Preferential translation of heat shock mRNAs in HeLa cells deficient in protein synthesis initiation factors eIF-4E and eIF-4 gamma [19].
• Interaction of eIF4G with poly(A)-binding protein stimulates translation and is critical for Xenopus oocyte maturation [20].
• In the reticulocyte lysate, eIF4G unable to interact directly with PABP showed little impairment in its ability to support translation, whereas loss of either of the eIF4A-binding sites or the eIF3-binding site resulted in a marked decrease in activity [21].

Associations of EIF4G1 with chemical compounds

• In this work, we demonstrate that the expression of the amino-terminal one-third of eIF4G, which interacts with eIF4E and PABP, in Xenopus oocyte inhibits translation and progesterone-induced maturation [22].
• The NH2- and COOH-terminal fragments of eIF-4 gamma were separated by reverse phase HPLC and identified with specific antibodies, and the NH2-terminal sequence of the COOH-terminal fragment was determined by automated Edman degradation [23].
• For example, eIF4G and eIF4E-binding proteins (4E-BPs) modulate cap affinity, and thus physiological activity of eIF4E, by binding a site distal to the 7-methylguanosine cap-binding site [24].
• Sucrose gradient sedimentation studies demonstrated that eIF-4 gamma was present on both 43 and 48 S initiation complexes but not 80 S complexes [25].
• Analysis of p220 from control and okadaic acid-treated cells demonstrated serine and threonine phosphorylation under both conditions [26].

Physical interactions of EIF4G1

• Here, we report that the pioneer round, which can be assessed by measuring NMD, is not inhibited by 4E-BP1, which is known to inhibit steady-state translation by competing with eIF4G for binding to eIF4E [27].
• In mammals, however, there has been no evidence that eIF4G binds PABP [14].
• A mutant adenovirus with a temperature-sensitive 100k protein that cannot inhibit cellular protein synthesis at restrictive temperature no longer blocks Mnk1 binding to eIF4G, or phosphorylation of eIF4E [2].
• Several eIF4A mutants showing wild-type level binding to Pdcd4 were also inactivated for binding to eIF4G and for enhancing translation [28].
• We demonstrate that all four AUF1 protein isoforms bind directly and strongly to initiation factor eIF4G at a C-terminal site regardless of AUF1 interaction with the ARE [29].

Enzymatic interactions of EIF4G1

• However, it was suggested that in poliovirus infection, the 2Apro induces the activation of a cellular proteinase which in turn cleaves eIF4G [30].
• Second, infusion of TNF-alpha for 24 h in control rats resulted in a 70% decrease in phosphorylated eIF4G [31].

Regulatory relationships of EIF4G1

• RNA interference releases Pak2-induced inhibition of translation in contact-inhibited cells by 2.7-fold. eIF4G mutants of the Pak2 site show that S896D inhibits translation, while S896A has no effect [32].
• The availability of eIF4E for binding to eIF4G is regulated by the phosphorylation of a small family of eIF4E-binding proteins (the 4E-BPs) [33].
• These data indicate that SLBP stimulates the translation of histone mRNAs through a functional interaction with both the mRNA stem-loop and the 5' cap that is mediated by eIF4G and eIF3 [34].
• Studies with the specific inhibitor, SB203580, have shown that signalling through the p38 MAP kinase pathway is not required for either the Fas/CD95-induced cleavage of eIF4G or cell death [35].
• Here, we report that based on antibody and mRNA reporter injection assays, maskin prevents oocyte maturation and the translation of the CPE-containing cyclin B1 mRNA by blocking the association of eIF4G with eIF4E [36].

Other interactions of EIF4G1

• Overexpression of Hsc70, a constitutive homolog of Hsp70, prevented loss of cap-initiation complexes and maintained eIF4G solubility [37].
• Thus, translational control by growth factors, insulin and mitogens is affected by changes in the relative affinities of 4E-BP1 and p220 for eIF-4E [38].
• Here we report that Mnk1 is associated with the eIF4F complex via its interaction with the C-terminal region of eIF4G [13].
• The N-terminal part of DAP-5 has 39% identity and 63% similarity to the central region of mammalian p220 [39].
• Here, we present evidence that eIF4G and the large subunit of the nuclear cap-binding complex, CBP80, share a common origin and domain structure [40].

Analytical, diagnostic and therapeutic context of EIF4G1

• Immunoprecipitation experiments suggest that, in contrast to the cytoplasmic pool, much of the nuclear eIF4G is not associated with eIF4E (translation cap binding protein of eIF4F) but is associated with CBC [18].
• Site-directed mutagenesis and isothermal titration calorimetry documented that NSP3 and PABP use analogous eIF4G recognition strategies, despite marked differences in tertiary structure [41].
• To examine further the role proteolysis of eIF4G plays in shut-off of translation, we altered the 2A cleavage site in human eIF4G by site-directed mutagenesis [42].
• In this study, we present genomic Southern blotting results which indicate that there is only a single gene, here designated EIF4G [43].
• Human eIF-4 gamma migrates as a cluster of polypeptides in the range of 200-220 kDa during SDS-PAGE, raising the possibility that it is a family of proteins encoded by separate genes [43].

References