EIF4E

Last updated
EIF4E
Protein EIF4E PDB 1ej1.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases EIF4E , eukaryotic translation initiation factor 4E, AUTS19, CBP, EIF4E1, EIF4EL1, EIF4F, eIF-4E
External IDs OMIM: 133440 MGI: 95305 HomoloGene: 123817 GeneCards: EIF4E
Orthologs
SpeciesHumanMouse
Entrez

1977

13684

Ensembl

ENSG00000151247

ENSMUSG00000028156

UniProt

P06730

P63073

RefSeq (mRNA)

NM_001130678
NM_001130679
NM_001968
NM_001331017

NM_007917
NM_001313980

RefSeq (protein)

NP_001124150
NP_001124151
NP_001317946
NP_001959

NP_001300909
NP_031943

Location (UCSC) Chr 4: 98.88 – 98.93 Mb Chr 3: 138.23 – 138.27 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
EIF4E with 7MetGTP EIF4E with 7MetGTP.png
EIF4E with 7MetGTP
4EBP (red) bound to the alpha helices (cyan) of eIF4E. EIF4E.png
4EBP (red) bound to the alpha helices (cyan) of eIF4E.

Eukaryotic translation initiation factor 4E, also known as eIF4E, is a protein that in humans is encoded by the EIF4E gene. [5] [6]

Structure and function

Most eukaryotic cellular mRNAs are blocked at their 5'-ends with the 7-methyl-guanosine five-prime cap structure, m7GpppX (where X is any nucleotide). This structure is involved in several cellular processes including enhanced translational efficiency, splicing, mRNA stability, and RNA nuclear export. eIF4E is a eukaryotic translation initiation factor involved in directing ribosomes to the cap structure of mRNAs as well as other steps in RNA metabolism that require cap-binding. It is a 24-kD polypeptide that exists as both a free form and as part of the eIF4F pre-initiation complex. [7] Many cellular mRNAs require eIF4E in order to be translated into protein. The eIF4E polypeptide is considered by some to be the rate-limiting component of the eukaryotic translation apparatus and is involved in the mRNA-ribosome binding step of eukaryotic protein synthesis.

The other subunits of eIF4F are a 47-kD polypeptide, termed eIF4A, [8] that possesses ATPase and RNA helicase activities, and a 220-kD scaffolding polypeptide, eIF4G. [9] [10] [11]

Some viruses cut eIF4G in such a way that the eIF4E binding site is removed and the virus is able to translate its proteins without eIF4E. Also some cellular proteins, the most notable being heat shock proteins, do not require eIF4E in order to be translated. Both viruses and cellular proteins achieve this through an internal ribosome entry site in the RNA or through other RNA translation mechanisms such as those going through eIF3d [12] [13]

eIF4E plays roles outside of translation and other cap-binding proteins can engage in cap-dependent translation in an eIF4E-independent manner including factors such as eIF3D, eIF3I, PARN, the nuclear cap-binding complex CBC. [14] [15] [12] [16] [17] [13] [18] Many of these appear to be dependent on both specific features of transcripts as well as cellular context.

eIF4E is found in the nucleus of many mammalian cell types as well as in other species including yeast, drosophila and humans. [19] [20] [21] [22] [23] [24] [25] [26] eIF4E is found in nuclear bodies a subset of which colocalize with PML nuclear bodies, and eIF4E is additionally found diffusely in parts of the nucleoplasm in mammalian. [23] [21] [24] [25] [27] [28] [26] In the nucleus, eIF4E plays well defined roles in the export of selected RNAs which contributes to its oncogenic phenotypes. [29] [21] [24] [25] [27] [28] [30] [31] [32] [33] This relies on the ability of eIF4E to bind the m7G cap of RNAs and the presence of the 50 nucleotide eIF4E sensitivity element (4ESE) in the 3’UTR of sensitive transcripts; although other elements may also play a role. This form of export relies on the CRM1/XPO1 pathway. [21] [24] [27] [34] [35] [26] Nuclear eIF4E has been shown to play other roles in RNA processing including in m7G capping, alternative polyadenylation and splicing. [36] [37] [38]

Increased nuclear accumulation of eIF4E as well as increased eIF4E-dependent RNA export, m7G capping and splicing of selected transcripts is characteristic of high-eIF4E AML patient samples. [25] [30] [38] [37] RNAs are selected based on USER codes, or cis-acting elements, within their RNAs for specific levels of RNA processing; thus not all transcripts are sensitive to all levels of regulation (including translation). [35] [39] [18] For its RNA export function, eIF4E directly binds to the leucine rich pentatricopeptide repeat protein (LRPPRC) which directly binds the dorsal surface of eIF4E and simultaneously to the 4ESE RNA thereby acting as a platform for assembly for the RNA export complex. [26] [35] The current model is then LRPPRC binds to CRM1/XPO1 to engage the nuclear pore and traffic the 4ESE RNA to the cytoplasm. [28] [26] [35] In all, the nuclear functions of eIF4E can have potent impacts on the proteome allowing eIF4E to both re-write the message as well as to increase production of proteins based on increased accumulation in the cytoplasm due to increased export as well as to increased number of ribosomes per transcript in some cases. Its multiple roles in RNA processing require its association of RNAs through the m7G cap, and thus eIF4E can be considered a cap-chaperone protein.

Regulation

Since eIF4E is an initiation factor that is relatively low in abundance, eIF4E can be controlled at multiple levels. [40] [18] Regulation of eIF4E may be achieved at the levels of transcription, RNA stability phosphorylation, subcellular localization and partner proteins. [41]

a. Regulation of eIF4E by Gene Expression and RNA stability

The mechanisms responsible for eIF4E transcriptional regulation are not entirely understood. However, several reports suggest a correlation between myc levels and eIF4E mRNA levels during the cell cycle. [42] The basis of this relationship was further established by the characterization of two myc-binding sites (CACGTG E box repeats) in the promoter region of the eIF4E gene. [43] This sequence motif is shared with other in vivo targets for myc and mutations in the E box repeats of eIF4E inactivated the promoter region, thereby diminishing its expression.

Recent studies shown that eIF4E levels can be regulated at transcriptional level by NFkB and C/EBP. [44] [45] Transduction of primary AML cells with IkB-SR resulted not only in reduction of eIF4E mRNA levels, but also re-localization of eIF4E protein. [25] eIF4E mRNA stability are also regulated by HuR and TIAR proteins. [46] [47] eIF4E gene amplification has been observed in subset of head and neck and breast cancer specimens. [48]

b. Regulation of eIF4E by Phosphorylation

Stimuli such as hormones, growth factors, and mitogens that promote cell proliferation also enhance translation rates by phosphorylating eIF4E. [49] Although eIF4E phosphorylation and translation rates are not always correlated, consistent patterns of eIF4E phosphorylation are observed throughout the cell cycle; wherein low phosphorylation is seen during G0 and M phase and wherein high phosphorylation is seen during G1 and S phase. [50] This evidence is further supported by the crystal structure of eIF4E which suggests that phosphorylation on serine residue 209 may increase the affinity of eIF4E for capped mRNA.

eIF4E phosphorylation is also related to its ability to suppress RNA export and its oncogenic potential as first shown in cell lines. [51]

c. Regulation of eIF4E by Partner Proteins

Assembly of the eIF4F complex is inhibited by proteins known as eIF4E-binding proteins (4E-BPs), which are small heat-stable proteins that block cap-dependent translation. [41] Non-phosphorylated 4E-BPs interact strongly with eIF4E thereby preventing translation; whereas phosphorylated 4E-BPs bind weakly to eIF4E and thus do not interfere with the process of translation. [52] Furthermore, binding of the 4E-BPs inhibits phosphorylation of Ser209 on eIF4E. [53] Of note, 4E-BP1 is found in both the nucleus and the cytoplasm, indicating that it likely modulates nuclear eIF4Es functions of eIF4E as well. [54] A recent study showed that 4E-BP3 regulated eIF4E dependent mRNA nucleo-cytoplasmic export. [55] There are also many cytoplasmic regulators of eIF4E that bind to the same site as 4E-BP1.

Many other partner proteins has been found that can both stimulate or repress eIF4E activity, such as  homeodomain containing proteins, including HoxA9, Hex/PRH, Hox 11, Bicoid, Emx-2 and Engrailed 2. [56] [24] [57] [58] [59] While HoxA9 promotes mRNA export and translation activities of eIF4E, Hex/PRH inhibits nuclear functions of eIF4E. [25] [60] [61] The RNA helicase DDX3 directly binds with eIF4E, modulates translation, and has potential functions in P-bodies and mRNA export. [62] [26]

RING domains also bind eIF4E. The promyelocytic leukemia protein PML is a potent suppressor of both the nuclear RNA export and oncogenic activities of eIF4E whereby the RING domain of PML directly binds eIF4E on its dorsal surface suppressing eIF4E's oncogenic activity; and moreover a subset of PML and eIF4E nuclear bodies co-localize. [63] [21] [64] [23] [24] [28] RNA-eIF4E complexes are never observed in PML bodies consistent with the observation that PML suppresses the m7G cap binding function of eIF4E. [21] [64] [28] Structural studies show that a related arenavirus RING finger protein, Lassa Fever Z protein, can similarly bind eIF4E on the dorsal surface. [64] [65] [66]

eIF4E nuclear entry is mediated by its direct interactions with Importin 8 where Importin 8 associates with the m7G cap-binding site of eIF4E. [32] Indeed, reduction in Importin 8 levels reduce the oncogenic potential of eIF4E overexpressing cells and its RNA export function. Importin 8 binds to the cap-binding site of eIF4E and is competed by excess m7G cap analogues as observed by NMR. eIF4E also stimulates the RNA export of Importin 8 RNA thereby producing more Importin 8 protein. There may be additional importins that play this role depending on cell type. Although an initial study suggested that the eIF4E transporter protein 4E-T (eIF4ENIF1) facilitated nuclear entry, later studies showed that this factor rather alters the localization of eIF4E to cytoplasmic processing bodies (P-bodies) and repress translation. [67]

Potyvirus viral protein genome linked (VPg) were found to directly bind eIF4E in its cap-binding site. VPg is covalently linked to its genomic RNA and this interaction allows VPg to act as a "cap." [68] [69] [16] [70] The potyvirus VPg has no sequence or structural homology to other VPg's such as those from poliovirus. In vitro, VPg-RNA conjugates were translated with similar efficiency to m7G-capped RNAs indicating that VPg binds eIF4E and engages the translation machinery; while free VPg (in the absence of conjugated RNA) successfully competes for all the cap-dependent activities of eIF4E in the cell inhibiting translation and  RNA export. [70]

d. Regulation of eIF4E cellular localization

Several factors that regulate eIF4E functions also modulate the subcellular localization of eIF4E. For instance, overexpression of PRH/Hex leads to cytoplasmic retention of eIF4E, and thus loss of its mRNA export activity and suppression of transformation. [24] PML overexpression leads to sequestration of eIF4E to nuclear bodies with PML and decrease of eIF4E nuclear bodies containing RNA, which correlates to repressed eIF4E dependent mRNA export and can be modulated by stress. [21] [23] [25] Overexpression of LRPPRC reduces eIF4E’s co-localization with PML in the nucleus and leads to increased mRNA export activity of eIF4E. As discussed above, Importin 8 brings eIF4E into the nucleus and its overexpression stimulates the RNA export and oncogenic tranformation activities of eIF4E in cell lines. Transduction of primary AML cells with IkB-SR resulted not only in reduction of eIF4E mRNA levels, but also re-localization of eIF4E protein. [25]

The Role of eIF4E in Cancer

The role of eIF4E in cancer was established after Lazaris-Karatzas et al. made the discovery that over-expressing eIF4E causes tumorigenic transformation of fibroblasts. [71] Since this initial observation, numerous groups have recapitulated these results in different cell lines. [72] As a result, eIF4E activity is implicated in several cancers including cancers of the breast, lung, and prostate. In fact, transcriptional profiling of metastatic human tumors has revealed a distinct metabolic signature wherein eIF4E is known to be consistently up-regulated. [73]

eIF4E levels are increased in many cancers including acute myeloid leukemia (AML), multiple myeloma, infant ALL, diffuse large B-cell lymphoma, breast cancer, prostate cancer, head and neck cancer and  its elevation generally correlates with poor prognosis. [30] [74] [75] [76] [77] [78] [79] [80] In many of these cancers such as AML, eIF4E is enriched in nuclei and several of eIF4E’s activities are found to be elevated in primary patient specimens, including capping, splicing, RNA export, and translation.

In the first clinical trials targeting eIF4E, old antiviral drug ribavirin was used as a m7G cap competitor which had substantial activity in cancer cell lines and animal models associated with dysregulated eIF4E. [81] [82] [75] [31] [83] [84] [85] [78] [86] [87] [88] [89] [90] [80] In the first trial to ever target eIF4E, ribavirin monotherapy was demonstrated to inhibit eIF4E activity leading to objective clinical responses including complete remissions in AML patients. [30] Interestingly, relocalization of eIF4E from the nucleus to the cytoplasm correlated with clinical remissions indicative of the relevance of its nuclear activities to disease progression. [30] Subsequent ribavirin trials in AML in combination with antileukemic drugs again showed objective clinical responses including remissions and molecular targeting of eIF4E. [76] [91]  Clinical responses correlated with reduced nuclear eIF4E and clinical relapse with re-emergence of eIF4E nuclear eIF4E and its RNA export activity in these AML studies. Other studies used ribavirin in combination showed similar promising results in  head and neck cancer. [79] Ribavirin impairs all of the activities of eIF4E examined to date (splicing, capping, RNA export and translation).  Thus, eIF4E has been successfully therapeutically targetable in humans; however drug resistance to ribavirin is an emergent problem to long term disease control. [84] [76] [91]

eIF4E has also been targeted by antisense oligonucleotides which were very potent in mouse models of prostate cancer, [92] but in monotherapy trials in humans did not provide clinical benefit likely due to the inefficiency of reducing eIF4E levels in humans compared to mice. [93] There is also an allosteric inhibitor of eIF4E which binds between the cap-binding site and the dorsal surface that is used experimentally. [94]

FMRP represses translation through EIF4E binding

Fragile X mental retardation protein (FMR1) acts to regulate translation of specific mRNAs through its binding of eIF4E. FMRP acts by binding CYFIP1, which directly binds eIF4e at a domain that is structurally similar to those found in 4E-BPs including EIF4EBP3, EIF4EBP1, and EIF4EBP2. The FMRP/CYFIP1 complex binds in such a way as to prevent the eIF4E-eIF4G interaction, which is necessary for translation to occur. The FMRP/CYFIP1/eIF4E interaction is strengthened by the presence of mRNA(s). In particular, BC1 RNA allows for an optimal interaction between FMRP and CYFIP1. [95] RNA-BC1 is a non-translatable, dendritic mRNA, which binds FMRP to allow for its association with a specific target mRNA. BC1 may function to regulate FMRP and mRNA interactions at synapse(s) through its recruitment of FMRP to the appropriate mRNA. [96]

In addition, FMRP may recruit CYFIP1 to specific mRNAs in order to repress translation. The FMRP-CYFIP1 translational inhibitor is regulated by stimulation of neuron(s). Increased synaptic stimulation resulted in the dissociation of eIF4E and CYFIP1, allowing for the initiation of translation. [95]

Interactions

EIF4E has been shown to interact with:

. Other direct interactors: PML; [21] [64] arenavirus Z protein; [64] [63] [65] [66] Importin 8; [32] potyvirus VPg protein, [70] LRPPRC, [35] [26] RNMT [117] and others.

See also

Related Research Articles

<span class="mw-page-title-main">Ribavirin</span> Antiviral medication

Ribavirin, also known as tribavirin, is an antiviral medication used to treat RSV infection, hepatitis C and some viral hemorrhagic fevers. For hepatitis C, it is used in combination with other medications such as simeprevir, sofosbuvir, peginterferon alfa-2b or peginterferon alfa-2a. Among the viral hemorrhagic fevers it is used for Lassa fever, Crimean–Congo hemorrhagic fever, and Hantavirus infection but should not be used for Ebola or Marburg infections. Ribavirin is taken by mouth or inhaled.

Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recapping.

Initiation factors are proteins that bind to the small subunit of the ribosome during the initiation of translation, a part of protein biosynthesis.

<span class="mw-page-title-main">Hepatitis A virus internal ribosome entry site (IRES)</span>

This family represents the internal ribosome entry site (IRES) of the hepatitis A virus. HAV IRES is a 450 nucleotide long sequence located in the 735 nt long 5’ UTR of Hepatitis A viral RNA genome. IRES elements allow cap and end-independent translation of mRNA in the host cell. The IRES achieves this by mediating the internal initiation of translation by recruiting a ribosomal 40S pre-initiation complex directly to the initiation codon and eliminates the requirement for eukaryotic initiation factor, eIF4F.

<span class="mw-page-title-main">EIF4EBP1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 4E-binding protein 1 is a protein that in humans is encoded by the EIF4EBP1 gene. inhibits cap-dependent translation by binding to translation initiation factor eIF4E. Phosphorylation of 4E-BP1 results in its release from eIF4E, thereby allows cap-dependent translation to continue thereby increasing the rate of protein synthesis.

<span class="mw-page-title-main">EIF4G2</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 4 gamma 2 is a protein that in humans is encoded by the EIF4G2 gene.

<span class="mw-page-title-main">Eukaryotic translation initiation factor 4 gamma 1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 4 gamma 1 is a protein that in humans is encoded by the EIF4G1 gene.

<span class="mw-page-title-main">MKNK1</span> Protein-coding gene in the species Homo sapiens

MAP kinase-interacting serine/threonine-protein kinase 1 is an enzyme that in humans is encoded by the MKNK1 gene.

<span class="mw-page-title-main">EIF4G3</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 4 gamma 3 is a protein that in humans is encoded by the EIF4G3 gene. The gene encodes a protein that functions in translation by aiding the assembly of the ribosome onto the messenger RNA template. Confusingly, this protein is usually referred to as eIF4GII, as although EIF4G3 is the third gene that is similar to eukaryotic translation initiation factor 4 gamma, the second isoform EIF4G2 is not an active translation initiation factor.

<span class="mw-page-title-main">EIF4A1</span> Protein coding gene in Humans

Eukaryotic initiation factor 4A-I is a 46 kDa cytosolic protein that, in humans, is encoded by the EIF4A1 gene, which is located on chromosome 17. It is the most prevalent member of the eIF4A family of ATP-dependant RNA helicases, and plays a critical role in the initiation of cap-dependent eukaryotic protein translation as a component of the eIF4F translation initiation complex. eIF4A1 unwinds the secondary structure of RNA within the 5'-UTR of mRNA, a critical step necessary for the recruitment of the 43S preinitiation complex, and thus the translation of protein in eukaryotes. It was first characterized in 1982 by Grifo, et al., who purified it from rabbit reticulocyte lysate.

<span class="mw-page-title-main">EIF4B</span> Protein-coding gene in humans

Eukaryotic translation initiation factor 4B is a protein that in humans is encoded by the EIF4B gene.

<span class="mw-page-title-main">EIF3D</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 3 subunit D (eIF3d) is a protein that in humans is encoded by the EIF3D gene.

<span class="mw-page-title-main">EIF4E2</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 4E type 2 is a protein that in humans is encoded by the EIF4E2 gene. It belongs to the eukaryotic translation initiation factor 4E family.

<span class="mw-page-title-main">EIF4ENIF1</span> Protein-coding gene in the species Homo sapiens

Eukaryotic translation initiation factor 4E transporter is a protein that in humans is encoded by the EIF4ENIF1 gene.

<span class="mw-page-title-main">EIF4EBP2</span> Protein-coding gene in humans

Eukaryotic translation initiation factor 4E-binding protein 2 is a protein that in humans is encoded by the EIF4EBP2 gene.

Nahum Sonenberg, is an Israeli Canadian microbiologist and biochemist. He is a James McGill professor of biochemistry at McGill University in Montreal, Quebec, Canada. He was an HHMI international research scholar from 1997 to 2011 and is now a senior international research scholar. He is best known for his seminal contributions to our understanding of translation, and notable for the discovery of the mRNA 5' cap-binding protein, eIF4E, the rate-limiting component of the eukaryotic translation apparatus.

Eukaryotic translation initiation factor 4 G (eIF4G) is a protein involved in eukaryotic translation initiation and is a component of the eIF4F cap-binding complex. Orthologs of eIF4G have been studied in multiple species, including humans, yeast, and wheat. However, eIF4G is exclusively found in domain Eukarya, and not in domains Bacteria or Archaea, which do not have capped mRNA. As such, eIF4G structure and function may vary between species, although the human EIF4G1 has been the focus of extensive studies.

The eukaryotic initiation factor-4A (eIF4A) family consists of 3 closely related proteins EIF4A1, EIF4A2, and EIF4A3. These factors are required for the binding of mRNA to 40S ribosomal subunits. In addition these proteins are helicases that function to unwind double-stranded RNA.

<span class="mw-page-title-main">Eukaryotic initiation factor 4F</span> Multiprotein complex used in gene expression

Eukaryotic initiation factor 4F (eIF4F) is a heterotrimeric protein complex that binds the 5' cap of messenger RNAs (mRNAs) to promote eukaryotic translation initiation. The eIF4F complex is composed of three non-identical subunits: the DEAD-box RNA helicase eIF4A, the cap-binding protein eIF4E, and the large "scaffold" protein eIF4G. The mammalian eIF4F complex was first described in 1983, and has been a major area of study into the molecular mechanisms of cap-dependent translation initiation ever since.

Katherine Borden PhD FRSC is a Canadian researcher of Molecular Biology and Biochemistry at the University of Montreal in Quebec, Canada. She has worked on finding new cancer treatments using pre-existing drugs,.She uses a combination of biochemistry, structural biology, cell biological, and clinical studies to study RNA processing. Her work provided a series of transformative revelations into the role of dysregulated RNA metabolism in cancer using the eukaryotic translation initiation factor eIF4E as an exemplar. Her studies demonstrated that dysregulation of this factor influenced multiple steps in RNA processing of thousands of RNAs simultaneously thereby reprogramming the cell to become more oncogenic. eIF4E impacts the extent of m7G RNA capping, splicing, export and/or translation of these RNAs based on the presence of cis-acting elements within the RNAs as well as induction of wide scale changes to the production of factors substantially modulated the RNA processing landscape within cells. Her work showed that modulating of many of these factors influence cell survival and cell motility contributing to cancer. Her studies also led to the finding that a substantial number of Acute Myeloid Leukemia (AML) patients were characterized by elevated eIF4E. This coupled to the discovery that eiF4E could bind to and be inhibited by an antiviral drug ribavirin led to the first clinical trials targeting eIF4E in patients. Indeed, these were also the first studies to target RNA translation or RNA export in humans. Targeting of eIF4E was safe and corresponded to objective clinical responses including remissions in patients. These studies also led to the discovery of a new form of drug resistance in patients, inducible drug glucuronidation. Drug glucuronidation impacts 50% of drugs usually through liver mediated drug deactivation. However, this work revealed that cancer cells could turn on the enzymes involved in this process. Her lab developed the means to target this inducible drug glucuronidation, with Vismodegib, and showed in patients this reduced levels of glucuronidation enzymes which corresponded to ribavirin activity, targeting of eIF4E and objective clinical responses. However, eventually patients become resistant to the Visomdegib and thus, new modalities are required to overcome this form of drug resistance long term. She has received many awards for this work including selected as a Stohlman Scholar of the Leukemia and Lymphoma Society USA (2005), Distinguished Scientist of the Canadian Society for Clinical Investigation (2011), CSMB Canadian Science Publishing Senior Investigator Award (2022) and was inducted as a fellow of the Royal Society of Canada in 2022.

References

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