EIF4B (eukaryotic translation initiation factor 4B)

2014-04-01   Thomas Sbarrato , Emilie Horvilleur , Tuija Pöyry , Anne E Willis 

Medical Research Council Toxicology Unit, Hodgkin Building, PO Box 138, Lancaster Rd, Leicester, LE1 9HN, UK




Review on eIF4B, with data on DNA\/RNA, on the protein encoded and where the gene is implicated.


Atlas Image
Figure 1: Schematic representation of eIF4B gene, which is composed of 15 exons shown in blue.


The eIF4B gene codes for EIF4B protein. eIF4B gene is 69.15 kb in length and is composed of 15 exons (Figure 1).


eIF4B mRNA is ubiquitously expressed, however, regulation of eIF4B transcription has not been studied in detail.


Atlas Image
Figure 2: Schematic representation of eIF4B protein. The numbers refer to amino acids flanking the functional domains. Ser406 and Ser422 that can be phosphorylated by several kinases are indicated.


eIF4B is a 79kDA protein composed of 611 residues. Many sites of phosphorylation have been found for this protein using proteomics tools, including 29 Ser, 13 Thr and 1 Tyr (Prasad et al., 2009). Among them, two have been validated by further studies. The best studied phosphorylation site is Ser422 by p70/S6kinase in response to mTOR pathway (Holz et al., 2005). Ser422 can also be phosphorylated by p90 (RSK) and PKB (Shahbazian et al., 2006; van Gorp et al., 2009). Ser406 phosphorylation is cell cycle dependent and under control of mTOR and MAP kinase pathways (van Gorp et al., 2009). Ser406 is a target of Pim kinases (Yang et al., 2013). Finally, eIF4B is cleaved by caspase 3 after Asp45 during apoptosis (Bushell et al., 2001) (Figure 2).


The protein is reported to be expressed in most tissues, excluding liver, smooth muscle or soft tissues (Uhlen et al., 2010). Given the crucial role played by this protein in the cell, it is expected to be expressed ubiquitously albeit probably to different levels throughout different tissues.


eIF4B has a cytoplasmic localisation.
Atlas Image
Figure 3: Initiation of translation.


eIF4B is an RNA binding protein involved in the regulation of the initiation stage of protein synthesis. This protein is critical for the recruitment of the mRNA to the ribosome. It helps unwind secondary structures in the mRNA to allow ribosome scanning, via enhancing both ATPase and helicase activities of eIF4A.
Translation of an mRNA initiates with the binding of eukaryotic initiation factor complex eIF4F comprised of eIF4E, eIF4G and eIF4A (Pestova and Kolupaeva, 2002) (Figure 3):
- eIF4E interacts directly with the cap of the mRNA and helps recruit the machinery to the 5end of the mRNA.
- eIF4G protein provides a scaffold, bridging interactions between eIF4A, eIF4E, eIF3, PABP and RNA.
- Secondary structures in the mRNA that can be detrimental to the binding/scanning of the ribosome are unwound by the helicase eIF4A and its cofactors eIF4B and eIF4H (Grifo et al., 1983; Lawson et al., 1989; Rozen et al., 1990).
The binding of this eIF4F complex allows for the circularisation of the mRNA and the subsequent recruitment of the 43S pre-initiation complex (PIC) composed of the small ribosomal subunit (40S), the ternary complex (eIF2/met-tRNA/GTP) and several initiation factors (eIF1, eIF1A, eIF3 and eIF5) (Deo et al., 1999; Imataka et al., 1998; Lamphear et al., 1995; Wells et al., 1998). This complex will then scan the untranslated region (UTR) of the mRNA until a start codon is recognised (Kozak, 2002).
eIF4B acts at different levels to stimulate translation initiation: 1) by enhancing the ATPase and helicase activities of eIF4A and 2) by facilitating the recruitment of the 43S PIC.

1) Role of eIF4B in the stimulation of eIF4A
Although the precise mechanisms of action of eIF4B on the enhanced helicase activity of eIF4F are not fully understood, knockdown/aberrant expression of eIF4B in mammalian cells led to the reduction/stimulation in translation of mRNAs containing highly structured 5UTRs (Horvilleur et al., 2013; Shahbazian et al., 2010). Additionally, the ATPase and helicase activity of free eIF4A was shown to be significantly slower than the rates of translation initiation or the rates of scanning of the PIC (Grifo et al., 1984; Pause et al., 1994; Richter-Cook et al., 1998).
Consequently, one can envisage that eIF4B can help in the substrate (ATP and RNA) recognition by eIF4A. As such, eIF4B can modulate the affinity for ATP and RNA by inducing conformational changes in eIF4A (Bi et al., 2000; Marintchev et al., 2009; Methot et al., 1994; Nielsen et al., 2011; Rogers Jr. et al., 2001; Rozovsky et al., 2008). Additionally, eIF4B can enhance the efficiency of this process by coupling the ATP hydrolysis to duplex unwinding to avoid redundant, energy-consuming events (Ozes et al., 2011). In a manner similar to other single-stranded DNA binding proteins that associate with helicases, one possible mode of action for eIF4B is to stabilize newly unwound single-stranded RNA. In support of this, a direct interaction between eIF4A and eIF4B in the presence of RNA and an ATP analog have been established via the C terminal region of eIF4B (Nielsen et al., 2011; Rozovsky et al., 2008).

2) Role of eIF4B in the recruitment of 43S PIC to mRNAs
Through its various domains, eIF4B is now known to promote the association of the various players in the recruitment of the 43S PIC to the mRNA. The C terminal RNA binding domain of eIF4B enables its binding to mRNA whereas the RRM motif triggers interaction with the rRNA from the 43S PIC (Methot et al., 1996a; Naranda et al., 1994). The latter is thought to anchor the helicase eIF4A to the scanning ribosome (Methot et al., 1996a). Importantly, mammalian eIF4B dimerises and binds to eIF3a via its DRYG repeats, thus providing a main link between the eIF4F-loaded mRNA and the 43S PIC (Methot et al., 1996b).
These results provide evidence that eIF4B participates in recruitment and assembly of the PIC on mRNAs. Critically, recent findings have now shown that interactions involving eIF4B via its different domains are essential for the effective assembly and efficient scanning of the 43S PIC. Yeast eIF4B together with eIF4F and eIF3 decreased the dependency on high concentrations of eIF4A for the rapid assembly and recruitment of the 43S PIC on endogenous short leader mRNAs (Mitchell et al., 2010; Walker et al., 2013), thus eIF4B can mediate an enhancing effect on the PIC recruitment to an mRNA.

The spatial positioning of eIF4B on the scanning ribosome is poorly understood. The helicase complex eIF4A/eIF4B could be located near the mRNA exit channel (i.e. 5/behind the scanning PIC) or alternatively at the mRNA entry channel (i.e. 3/in front of the scanning PIC) (Figure 4). To support the former hypothesis, a Brownian ratchet model was proposed in which eIF4F is located near the exit channel of the PIC (Spirin, 2009). In this model, eIF4A-unwound and eIF4B-captured single-stranded RNA would be scanned by diffusion by the PIC. Contradictory, new evidence have shown that yeast eIF4B mapped to the head of the PIC near the entry channel (Walker et al., 2013). In such a case, the eIF4F complex would be recruited to the cap and would be located at the forefront of the PIC, thus allowing efficient unwinding and scanning (Marintchev et al., 2009). New experimental approaches, including structures of the human ribosome associated with factors, should be able to shed some light on the matter in the future.

Atlas Image
Figure 4: Two possible models for eIF4B position in the initiation complex during scanning of 5UTR.


eIF4B is one of the least conserved initiation factors in terms of sequence homology (Cheng and Gallie, 2006), however, its function is conserved and eIF4B homologues can be found across all eukaryotic species. In addition to the human eIF4B, one of the most studied eIF4B homologs is the yeast protein, TIF3 (Altmann et al., 1993). eIF4H is a 23kDa paralog of eIF4B showing homology to the RRM RNA binding domain. eIF4H stimulates eIF4A helicase activity in a similar way to eIF4B.

Implicated in

Entity name
General role in cancer
eIF4B expression and phosphorylation are de-regulated in many cancers. In particular, Ser422 phosphorylation is at the crossroad of two major pathways in oncogenesis: MAP kinases and AKT/mTOR pathway (Shahbazian et al., 2006) (Figure 5). In response to these signalling pathways, eIF4B activates both global translation, driving faster proliferation, and overexpression of specific oncoproteins such as MYC or BCL2 (Shahbazian et al., 2010). Activation of eIF4B and subsequent c-MYC induction is involved in arsenic-induced transformation in mouse epithelial cells (Zhang et al., 2011). Moreover, binding of 14-3-3 sigma tumour suppressor to eIF4B in late mitosis regulates translation indicating direct involvement of eIF4B in regulation of cell cycle (Wilker et al., 2007). Finally, eIF4B is cleaved by a caspase dependent mechanism upon activation of tumour necrosis factor pathway, suggesting a role in preventing apoptosis (Jeffrey et al., 2002).
Atlas Image
Figure 5: mTOR and MEK/ERK/MAP kinase pathways converge on eIF4B.
Entity name
Nasopharyngeal carcinoma (NPC)
Although not mutated, p53 is known to be up-regulated in NPC. In a proteomic study, eIF4B was shown to be down-regulated following p53 knockdown in a NPC cell line (Sun et al., 2007).
Entity name
T-cell lymphoblastic leukemia/lymphoma
eIF4B mRNA was found to be up-regulated in a genome wide study comparing mouse model of thymic tumours (lymphoblastic leukaemia precursor) to untransformed thymus (Lin and Aplan, 2007).
Entity name
Gastric cancer
A microarray study found eIF4B mRNA to be up-regulated in a panel of 22 patients after they became resistant to combined cisplatin and fludarabine treatment (Kim et al., 2011).
Entity name
Non-small cell lung cancer (NSCLC)
Chromosomal aberrations in 12q13 region are frequent in NSCLC, where there can be either loss of heterozygocity or amplification, sometimes coupled with unbalanced translocation. eIF4B expression is significantly higher in NSCLC tumours showing this kind of alteration (Liang et al., 2013). Synergistic effect of mTOR and MEK inhibitors in NSCLC cell lines is correlated with significant decrease in eIF4B phosphorylation (Zou et al., 2012).
Entity name
Oral squamous cell carcinoma
Activation of Laminin γ2 by eIF4B is found in pre-malignant oral dysplasia, where eIF4B is activated by ERK/MAP kinase pathway (Degen et al., 2012). Laminin γ2 levels remain high in oral squamous cell carcinoma, although eIF4B has not been studied in this context.
Entity name
Prostatic cancer
In Prostatic carcinoma, eIF4B phosphorylation by Pim2 leads to resistance to apoptosis (Ren et al., 2013).
Entity name
eIF4B phosphorylation increased following activation of mTOR pathway in lymphangioleiomyomatosis (Gu et al., 2013).
eIF4B is up-regulated following activation of mTOR pathway in DLBCL and, in turn, activates translation of proteins involved in DNA repair and inhibition of apoptosis. Elevated eIF4B level was shown to be poor prognosis in DLBCL (Horvilleur et al., 2013).
Entity name
Various cancers
Finally, amplification, duplication and deletion of 12q13 have been described in different cancers including sarcoma, glioma, bladder carcinoma or anaplastic lymphoma without direct involvement of eIF4B.


Pubmed IDLast YearTitleAuthors
84048651993A Saccharomyces cerevisiae homologue of mammalian translation initiation factor 4B contributes to RNA helicase activity.Altmann M et al
108013262000Wheat germ translation initiation factor eIF4B affects eIF4A and eIFiso4F helicase activity by increasing the ATP binding affinity of eIF4A.Bi X et al
112741522001Disruption of the interaction of mammalian protein synthesis eukaryotic initiation factor 4B with the poly(A)-binding protein by caspase- and viral protease-mediated cleavages.Bushell M et al
168038752006Wheat eukaryotic initiation factor 4B organizes assembly of RNA and eIFiso4G, eIF4A, and poly(A)-binding protein.Cheng S et al
225464782012MAPK/ERK-dependent translation factor hyperactivation and dysregulated laminin γ2 expression in oral dysplasia and squamous cell carcinoma.Degen M et al
104998001999Recognition of polyadenylate RNA by the poly(A)-binding protein.Deo RC et al
61457161984RNA-stimulated ATPase activity of eukaryotic initiation factors.Grifo JA et al
68535481983New initiation factor activity required for globin mRNA translation.Grifo JA et al
239832652013Integration of mTOR and estrogen-ERK2 signaling in lymphangioleiomyomatosis pathogenesis.Gu X et al
162860062005mTOR and S6K1 mediate assembly of the translation preinitiation complex through dynamic protein interchange and ordered phosphorylation events.Holz MK et al
241358292014A role for eukaryotic initiation factor 4B overexpression in the pathogenesis of diffuse large B-cell lymphoma.Horvilleur E et al
98572021998A newly identified N-terminal amino acid sequence of human eIF4G binds poly(A)-binding protein and functions in poly(A)-dependent translation.Imataka H et al
119560832002Inhibition of protein synthesis in apoptosis: differential requirements by the tumor necrosis factor alpha family and a DNA-damaging agent for caspases and the double-stranded RNA-dependent protein kinase.Jeffrey IW et al
213647532011A gene expression signature of acquired chemoresistance to cisplatin and fluorouracil combination chemotherapy in gastric cancer patients.Kim HK et al
124592502002Pushing the limits of the scanning mechanism for initiation of translation.Kozak M et al
76656191995Mapping of functional domains in eukaryotic protein synthesis initiation factor 4G (eIF4G) with picornaviral proteases. Implications for cap-dependent and cap-independent translational initiation.Lamphear BJ et al
25485911989Dissociation of double-stranded polynucleotide helical structures by eukaryotic initiation factors, as revealed by a novel assay.Lawson TG et al
232253322013Analysis of 20 genes at chromosome band 12q13: RACGAP1 and MCRS1 overexpression in nonsmall-cell lung cancer.Liang Y et al
174294292007Gene expression profiling of precursor T-cell lymphoblastic leukemia/lymphoma identifies oncogenic pathways that are potential therapeutic targets.Lin YW et al
192035802009Topology and regulation of the human eIF4A/4G/4H helicase complex in translation initiation.Marintchev A et al
81395361994The translation initiation factor eIF-4B contains an RNA-binding region that is distinct and independent from its ribonucleoprotein consensus sequence.Méthot N et al
88462951996In vitro RNA selection identifies RNA ligands that specifically bind to eukaryotic translation initiation factor 4B: the role of the RNA remotif.Methot N et al
88164441996A region rich in aspartic acid, arginine, tyrosine, and glycine (DRYG) mediates eukaryotic initiation factor 4B (eIF4B) self-association and interaction with eIF3.Méthot N et al
208640402010The 5'-7-methylguanosine cap on eukaryotic mRNAs serves both to stimulate canonical translation initiation and to block an alternative pathway.Mitchell SF et al
81820511994Two structural domains of initiation factor eIF-4B are involved in binding to RNA.Naranda T et al
211130242011Synergistic activation of eIF4A by eIF4B and eIF4G.Nielsen KH et al
218403182011Duplex unwinding and ATPase activities of the DEAD-box helicase eIF4A are coupled by eIF4G and eIF4B.Özeş AR et al
81317501994Dominant negative mutants of mammalian translation initiation factor eIF-4A define a critical role for eIF-4F in cap-dependent and cap-independent initiation of translation.Pause A et al
124356322002The roles of individual eukaryotic translation initiation factors in ribosomal scanning and initiation codon selection.Pestova TV et al
197185092009Human Protein Reference Database and Human Proteinpedia as discovery tools for systems biology.Prasad TS et al
238136712013The over-expression of Pim-2 promote the tumorigenesis of prostatic carcinoma through phosphorylating eIF4B.Ren K et al
95164611998Purification and characterization of a new eukaryotic protein translation factor. Eukaryotic initiation factor 4H.Richter-Cook NJ et al
114185882001Modulation of the helicase activity of eIF4A by eIF4B, eIF4H, and eIF4F.Rogers GW Jr et al
23044611990Bidirectional RNA helicase activity of eucaryotic translation initiation factors 4A and 4F.Rozen F et al
187192482008Interactions between eIF4AI and its accessory factors eIF4B and eIF4H.Rozovsky N et al
200861002010Control of cell survival and proliferation by mammalian eukaryotic initiation factor 4B.Shahbazian D et al
171847792007Identification of differential proteins in nasopharyngeal carcinoma cells with p53 silence by proteome analysis.Sun Y et al
211396052010Towards a knowledge-based Human Protein Atlas.Uhlen M et al
232361922013Yeast eIF4B binds to the head of the 40S ribosomal subunit and promotes mRNA recruitment through its N-terminal and internal repeat domains.Walker SE et al
97022001998Circularization of mRNA by eukaryotic translation initiation factors.Wells SE et al
17361185200714-3-3sigma controls mitotic translation to facilitate cytokinesis.Wilker EW et al
237496392013eIF4B phosphorylation by pim kinases plays a critical role in cellular transformation by Abl oncogenes.Yang J et al
212681302011Activation and up-regulation of translation initiation factor 4B contribute to arsenic-induced transformation.Zhang Y et al
221014212012The novel dual PI3K/mTOR inhibitor GDC-0941 synergizes with the MEK inhibitor U0126 in non-small cell lung cancer cells.Zou ZQ et al
188364822009AGC kinases regulate phosphorylation and activation of eukaryotic translation initiation factor 4B.van Gorp AG et al

Other Information

Locus ID:

NCBI: 1975
MIM: 603928
HGNC: 3285
Ensembl: ENSG00000063046


dbSNP: 1975
ClinVar: 1975
TCGA: ENSG00000063046


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
mTOR signaling pathwayKEGGko04150
mTOR signaling pathwayKEGGhsa04150
RNA transportKEGGko03013
RNA transportKEGGhsa03013
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
Metabolism of proteinsREACTOMER-HSA-392499
Eukaryotic Translation InitiationREACTOMER-HSA-72613
Cap-dependent Translation InitiationREACTOMER-HSA-72737
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43SREACTOMER-HSA-72662
Translation initiation complex formationREACTOMER-HSA-72649
Ribosomal scanning and start codon recognitionREACTOMER-HSA-72702
GTP hydrolysis and joining of the 60S ribosomal subunitREACTOMER-HSA-72706
L13a-mediated translational silencing of Ceruloplasmin expressionREACTOMER-HSA-156827
Signal TransductionREACTOMER-HSA-162582
Signaling by Insulin receptorREACTOMER-HSA-74752
Insulin receptor signalling cascadeREACTOMER-HSA-74751
IRS-mediated signallingREACTOMER-HSA-112399
PI3K CascadeREACTOMER-HSA-109704
PKB-mediated eventsREACTOMER-HSA-109703
mTOR signallingREACTOMER-HSA-165159
mTORC1-mediated signallingREACTOMER-HSA-166208
Signaling by Type 1 Insulin-like Growth Factor 1 Receptor (IGF1R)REACTOMER-HSA-2404192
IGF1R signaling cascadeREACTOMER-HSA-2428924
IRS-related events triggered by IGF1RREACTOMER-HSA-2428928
Gene ExpressionREACTOMER-HSA-74160
Deadenylation-dependent mRNA decayREACTOMER-HSA-429914
Deadenylation of mRNAREACTOMER-HSA-429947

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
167635662006The mTOR/PI3K and MAPK pathways converge on eIF4B to control its phosphorylation and activity.165
150715002004Phosphorylation of eucaryotic translation initiation factor 4B Ser422 is modulated by S6 kinases.152
214277652011mRNA helicases: the tacticians of translational control.146
252200532014The mTORC1/S6K1 pathway regulates glutamine metabolism through the eIF4B-dependent control of c-Myc translation.75
193694212009Uncoupling stress granule assembly and translation initiation inhibition.69
150789512004Herpes simplex virus virion host shutoff protein is stimulated by translation initiation factors eIF4B and eIF4H.40
218403182011Duplex unwinding and ATPase activities of the DEAD-box helicase eIF4A are coupled by eIF4G and eIF4B.40
187192482008Interactions between eIF4AI and its accessory factors eIF4B and eIF4H.39
219949502011Phosphorylation of eukaryotic translation initiation factor 4B (EIF4B) by open reading frame 45/p90 ribosomal S6 kinase (ORF45/RSK) signaling axis facilitates protein translation during Kaposi sarcoma-associated herpesvirus (KSHV) lytic replication.32
248293572014Influenza A virus-induced degradation of eukaryotic translation initiation factor 4B contributes to viral replication by suppressing IFITM3 protein expression.28


Thomas Sbarrato ; Emilie Horvilleur ; Tuija Pöyry ; Anne E Willis

EIF4B (eukaryotic translation initiation factor 4B)

Atlas Genet Cytogenet Oncol Haematol. 2014-04-01

Online version: http://atlasgeneticsoncology.org/gene/53571/eif4b-(eukaryotic-translation-initiation-factor-4b)