Existing Annotations Review

Core Functions

EIF3E is an integral component of the 13-subunit human eIF3 complex, forming part of module C with EIF3C, EIF3D, EIF3K, and EIF3L. It contributes to translation initiation factor activity as part of the eIF3 complex, which is required for 43S and 48S preinitiation complex formation and mRNA recruitment to the ribosome.

Molecular Function:

translation initiation factor activity

Directly Involved In:

translational initiation

Cellular Locations:

cytosol

In Complex:

eukaryotic translation initiation factor 3 complex

EIF3E participates in mRNA-selective translation regulation. The eIF3 complex can both activate (e.g., c-Jun) and repress (e.g., BTG1) translation of specific mRNAs through binding to 5' UTR stem-loop structures.

Molecular Function:

translation initiation factor activity

Directly Involved In:

regulation of translational initiation positive regulation of translation

EIF3E is uniquely required for nonsense-mediated mRNA decay (NMD). It interacts with CBP80 and UPF2 to function in pioneer round translation, specifically targeting NMD substrates without affecting general translation.

Molecular Function:

translation initiation factor activity

Directly Involved In:

nuclear-transcribed mRNA catabolic process, nonsense-mediated decay

Cellular Locations:

nucleus PML body

References

GO_REF:0000024

Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity.

GO_REF:0000033

Annotation inferences using phylogenetic trees

EIF3E is a conserved eIF3 subunit with orthologs across eukaryotes supporting translational initiation function

GO_REF:0000043

Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping

GO_REF:0000044

Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping

GO_REF:0000052

Gene Ontology annotation based on curation of immunofluorescence data

GO_REF:0000104

Electronic Gene Ontology annotations created by transferring manual GO annotations between related proteins based on shared sequence features

GO_REF:0000107

Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara

GO_REF:0000117

Electronic Gene Ontology annotations created by ARBA machine learning models

GO_REF:0000120

Combined Automated Annotation using Multiple IEA Methods

PMID:9295280

The translation initiation factor eIF3-p48 subunit is encoded by int-6, a site of frequent integration by the mouse mammary tumor virus genome

Original identification of EIF3E as the p48 subunit of human eIF3
Interaction with EIF3A demonstrated
Ubiquitous tissue expression

PMID:10504338

Interaction between the Ret finger protein and the Int-6 gene product and co-localisation into nuclear bodies

EIF3E interacts with TRIM27 (Ret finger protein) and EIF3C
Nuclear and cytoplasmic localization demonstrated by immunofluorescence
Co-localization with PML bodies in nucleus

PMID:16920360

eIF3: a versatile scaffold for translation initiation complexes

Review describing eIF3 structure and function
eIF3 serves as scaffold for translation initiation complex assembly

PMID:17322308

Structural characterization of the human eukaryotic initiation factor 3 protein complex by mass spectrometry

Mass spectrometry identification of all 13 eIF3 subunits
EIF3E confirmed as integral component
N-terminal acetylation of EIF3E

PMID:17468741

Human INT6/eIF3e is required for nonsense-mediated mRNA decay

EIF3E is specifically required for NMD
EIF3E interacts with CBP80 and UPF2
EIF3E functions in pioneer round translation
EIF3E knockdown inhibits NMD without affecting general translation

PMID:17581632

Reconstitution reveals the functional core of mammalian eIF3

Six-subunit complex including EIF3E has translation initiation activity
EIF3E is essential for eIF3 complex assembly and function

PMID:18599441

Mass spectrometry reveals modularity and a complete subunit interaction map of the eukaryotic translation factor eIF3

Complete eIF3 subunit interaction map
EIF3E is part of module C with EIF3C, EIF3D, EIF3K, EIF3L
EIF3E interacts directly with EIF3B, EIF3D, EIF3K, EIF3L

PMID:23623729

Architecture of human translation initiation factor 3

Cross-linking mass spectrometry of eIF3 architecture
Spatial organization of EIF3E within the complex

PMID:24092755

Human eukaryotic initiation factor 4G (eIF4G) protein binds to eIF3c, -d, and -e to promote mRNA recruitment to the ribosome

EIF3E interacts with eIF4G
This interaction promotes mRNA recruitment to ribosomes

PMID:25849773

eIF3 targets cell-proliferation messenger RNAs for translational activation or repression

eIF3 selectively regulates translation of specific mRNAs
eIF3 can both activate and repress translation of target mRNAs
c-Jun mRNA translation is activated by eIF3
BTG1 mRNA translation is repressed by eIF3

PMID:16189514

Towards a proteome-scale map of the human protein-protein interaction network

PMID:17324924

Mammalian tumor suppressor Int6 specifically targets hypoxia inducible factor 2 alpha for degradation by hypoxia- and pVHL-independent regulation

PMID:17353931

Large-scale mapping of human protein-protein interactions by mass spectrometry

PMID:18628297

Human DDX3 functions in translation and interacts with the translation initiation factor eIF3

PMID:19748344

Subunit architecture of multiprotein assemblies determined using restraints from gas-phase measurements

PMID:20890303

Int6 regulates both proteasomal degradation and translation initiation and is critical for proper formation of acini by human mammary epithelium

PMID:21988832

Toward an understanding of the protein interaction network of the human liver

PMID:22190034

Global landscape of HIV-human protein complexes

PMID:24705354

The palmitoyl acyltransferase HIP14 shares a high proportion of interactors with huntingtin: implications for a role in the pathogenesis of Huntington's disease.

PMID:25416956

A proteome-scale map of the human interactome network

PMID:26496610

A human interactome in three quantitative dimensions organized by stoichiometries and abundances

PMID:28514442

Architecture of the human interactome defines protein communities and disease networks

PMID:30833792

A protein-interaction network of interferon-stimulated genes extends the innate immune system landscape

PMID:31515488

Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations

PMID:32296183

A reference map of the human binary protein interactome

PMID:32814053

Interactome Mapping Provides a Network of Neurodegenerative Disease Proteins and Uncovers Widespread Protein Aggregation in Affected Brains

PMID:33961781

Dual proteome-scale networks reveal cell-specific remodeling of the human interactome

PMID:35271311

OpenCell: Endogenous tagging for the cartography of human cellular organization

PMID:39251607

Systematic identification of post-transcriptional regulatory modules

PMID:21745818

Mechanisms of translational regulation by a human eIF5-mimic protein

PMID:25468996

E-cadherin interactome complexity and robustness resolved by quantitative proteomics

PMID:19946888

Defining the membrane proteome of NK cells

PMID:22681889

The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts

PMID:20458337

MHC class II-associated proteins in B-cell exosomes and potential functional implications for exosome biogenesis

Reactome:R-HSA-156808

Formation of translation initiation complexes yielding circularized Ceruloplasmin mRNA in a closed-loop conformation

Reactome:R-HSA-156823

Association of phospho-L13a with GAIT element of Ceruloplasmin mRNA

Reactome:R-HSA-157849

Formation of translation initiation complexes containing mRNA that does not circularize

Reactome:R-HSA-72619

eIF2-GTP is hydrolyzed, eIFs are released

Reactome:R-HSA-72621

Ribosomal scanning

Reactome:R-HSA-72676

eIF3 and eIF1A bind to the 40S subunit

Reactome:R-HSA-72691

Formation of the 43S pre-initiation complex

Reactome:R-HSA-72697

Start codon recognition

file:human/EIF3E/EIF3E-deep-research-perplexity.md

Deep research on EIF3E function

Suggested Experiments

Experiment: Determine cryo-EM structures of EIF3E-containing eIF3 bound to specific target mRNAs to reveal how EIF3E contributes to mRNA-selective translation regulation.

Experiment: Perform proximity labeling (BioID/APEX) of nuclear versus cytoplasmic EIF3E pools to identify compartment-specific interaction partners and functions.

Experiment: Conduct ribosome profiling after acute EIF3E depletion to identify the specific mRNAs whose translation depends on EIF3E.

Deep Research

Falcon

(EIF3E-deep-research-falcon.md)

this with annotations you find in gene/protein databases, but these can be outdated or inaccurate. Falcon Edison Scientific Literature 9 citations 2025-12-14T17:20:47.345105

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

Research report: Human EIF3E (eIF3e/INT6; UniProt P60228)

Verification of identity and context
- Target verified: human EIF3E (aliases eIF3e/INT6/EIF3S6), UniProt P60228. EIF3E is a PCI-domain subunit of the eIF3 complex, consistent with its placement in the PCI-containing octameric module of eIF3. This aligns with recent structural/organizational descriptions of human eIF3 (PCI/octamer architecture). (duan2023eif3mrnaselectivity pages 26-26)

Key concepts and definitions (current understanding)
- Definition and role: EIF3E encodes eIF3e, a PCI-domain–containing subunit of the human eukaryotic translation initiation factor 3 (eIF3) complex. eIF3e participates in assembly/stability of the eIF3 octamer and contributes to bridging cap-recognition machinery to the 43S/48S pre-initiation complex (PIC), thereby supporting mRNA-selective initiation. (duan2023eif3mrnaselectivity pages 1-2, choi2024repressionofmrna pages 1-2, duan2023eif3mrnaselectivity pages 26-26)
- Functional module with eIF3d: eIF3e forms a functional d–e module with eIF3d. This module promotes selective translation of cohorts of mRNAs encoding membrane-associated and mitochondrial proteins and contributes to early steps in their translation. (Duan et al., EMBO J, May 2023; URL: https://doi.org/10.15252/embj.2022112362) (duan2023eif3mrnaselectivity pages 1-2)
- Gatekeeper of initiation fidelity and transcript selectivity: Core eIF3 subunits, including eIF3e, modulate start codon fidelity in human cells; depletion of core eIF3 subunits promotes near-cognate start codon usage, indicating a role for eIF3 in accurate initiation site selection. (She et al., Nucleic Acids Res, May 2023; URL: https://doi.org/10.1093/nar/gkad329) (duan2023eif3mrnaselectivity pages 26-26)

EIF3E (eIF3e/INT6): concise definition
EIF3E (UniProt P60228) is a PCI-domain subunit of the eIF3 translation initiation complex and forms part of the PCI-containing octamer of peripheral subunits. (duan2023eif3mrnaselectivity pages 26-26, duan2023eif3mrnaselectivity pages 1-2)
It functionally partners with eIF3d as a d–e module that selectively promotes translation of membrane- and mitochondrial-associated proteins and contributes to early steps of their translation. (duan2023eif3mrnaselectivity pages 1-2)
Acute depletion of eIF3e remodels the translatome—reducing translation of MAPK pathway components while increasing translation of TOP mRNAs encoding ribosomal proteins—showing transcript-selective roles in initiation and homeostatic responses. (herrmannova2024perturbationsineif3 pages 1-2)
Mechanistically, eIF3 operates at the eIF3–eIF4G1 interface that bridges cap-binding machinery to the 43S/48S PIC, and eIF3d-dependent, eIF4E-independent cap recognition provides an alternative initiation route in which eIF3e serves as a structural partner. (choi2024repressionofmrna pages 1-2, duan2023eif3mrnaselectivity pages 26-26)

Blockquote: A 4-sentence, citation-backed concise definition summarizing human EIF3E's domain architecture, eIF3 complex membership, functional partnership with eIF3d, translatome effects upon depletion, and mechanistic placement at the eIF3–eIF4G1/eIF3d axis; useful as a quick reference anchored to 2023–2024 sources.

Recent developments and latest research (emphasis 2023–2024)
- Translatome remodeling upon eIF3e depletion: Ribo-seq in HeLa cells showed that acute depletion of eIF3e reduces translation of multiple MAPK pathway components yet paradoxically increases MAPK/ERK signaling activity. eIF3e depletion also increases translation of TOP mRNAs encoding ribosomal proteins and other translational machinery components, and modulates mRNAs with short uORFs (e.g., MDM2, ATF4). These data highlight mRNA-selective regulatory roles of eIF3e in stress/homeostatic adaptation. (Herrmannová et al., eLife, Nov 2024; URL: https://doi.org/10.7554/elife.95846) (herrmannova2024perturbationsineif3 pages 1-2)
- Mechanistic interface with eIF4G1: GIGYF1 can repress translation initiation by binding eIF3 at the eIF3–eIF4G1 interaction interface, disrupting eIF3 binding to eIF4G1. This places eIF3 subunits (including eIF3e) at a critical mechanistic junction that regulates cap-dependent translation via the eIF3–eIF4G1 bridge. (Choi et al., Sci Adv, Jul 2024; URL: https://doi.org/10.1126/sciadv.adl5638) (choi2024repressionofmrna pages 1-2)
- Alternative cap recognition under stress: eIF4E1-independent translation of a subset of mRNAs is largely eIF3d-dependent via an eIF3d cap-binding pocket. This delineates an alternative cap-recognition route through eIF3, consistent with eIF3e partnering with eIF3d within the complex. (Roiuk et al., Nat Commun, Aug 2024; URL: https://doi.org/10.1038/s41467-024-51027-z) (duan2023eif3mrnaselectivity pages 26-26)
- eIF3e–eIF3d module and selective translation: eIF3e supports selective translation of membrane/mitochondrial protein mRNAs in human cells, reinforcing the concept of subunit-specific mRNA selectivity within eIF3. Endogenous tagging showed predominantly cytoplasmic localization, consistent with roles at ribosomes/polysomes. (Duan et al., EMBO J, May 2023; URL: https://doi.org/10.15252/embj.2022112362) (duan2023eif3mrnaselectivity pages 1-2)

Current applications and real-world implementations
- Functional genomics and disease-relevant translation programs: Acute depletion paradigms (AID-tagging/CRISPRi; Ribo-seq) are used to interrogate eIF3e’s contribution to oncogenic pathways (MAPK) and translational capacity (TOP mRNAs), offering actionable readouts for pathway modulation in cancer biology. (Herrmannová et al., eLife, 2024; URL: https://doi.org/10.7554/elife.95846) (herrmannova2024perturbationsineif3 pages 1-2)
- Targeting initiation interfaces: The demonstration that RBPs such as GIGYF1 repress initiation by interfering with the eIF3–eIF4G1 interface suggests potential for small-molecule or biologic strategies to modulate this interface, impacting transcripts under eIF3-mediated control. (Choi et al., Sci Adv, 2024; URL: https://doi.org/10.1126/sciadv.adl5638) (choi2024repressionofmrna pages 1-2)
- Stress and alternative initiation: Recognition that eIF3d-mediated cap recognition can sustain translation when eIF4E is inhibited provides a rationale for context-specific therapeutic strategies that consider eIF3-driven initiation modes (e.g., hypoxia, mTORC1 inactivation). (Roiuk et al., Nat Commun, 2024; URL: https://doi.org/10.1038/s41467-024-51027-z) (duan2023eif3mrnaselectivity pages 26-26)

Expert opinions and analysis from authoritative sources
- EMBO Journal and eLife studies support a model in which individual eIF3 subunits are not universally essential but carry distinct, transcript-selective functions; eIF3e lies within a module with eIF3d that shapes mitochondrial/membrane protein synthesis and influences early translational steps. These expert-led studies endorse moving beyond a monolithic view of eIF3 toward subunit-resolved biology with disease relevance. (Duan et al., EMBO J, 2023; URL: https://doi.org/10.15252/embj.2022112362) (duan2023eif3mrnaselectivity pages 1-2) (Herrmannová et al., eLife, 2024; URL: https://doi.org/10.7554/elife.95846) (herrmannova2024perturbationsineif3 pages 1-2)
- The Nucleic Acids Research CRISPRi screens emphasize eIF3 core subunits (including eIF3e) as regulators of start codon selectivity, reinforcing their gatekeeping role in initiation fidelity—a position echoed by mechanistic mapping of the eIF3–eIF4G1 interface. (She et al., Nucleic Acids Res, 2023; URL: https://doi.org/10.1093/nar/gkad329) (duan2023eif3mrnaselectivity pages 26-26) (Choi et al., Sci Adv, 2024; URL: https://doi.org/10.1126/sciadv.adl5638) (choi2024repressionofmrna pages 1-2)

Relevant statistics and data from recent studies
- Translatome effects: In HeLa cells, eIF3e depletion by RNAi followed by Ribo-seq reduced translation of multiple MAPK pathway components while increasing translation of TOP mRNAs encoding ribosomal proteins and other translational machinery; specific gene-level examples include effects on MDM2 and ATF4 uORF-regulated transcripts. (Herrmannová et al., eLife, Nov 2024; URL: https://doi.org/10.7554/elife.95846) (herrmannova2024perturbationsineif3 pages 1-2)
- Initiation fidelity screens: Genome-wide CRISPRi in K562 cells found that depletion of core eIF3 subunits—eIF3e among them—promoted near-cognate start codon usage, indicating quantifiable shifts in start-site selection upon eIF3 perturbation. (She et al., Nucleic Acids Res, May 2023; URL: https://doi.org/10.1093/nar/gkad329) (duan2023eif3mrnaselectivity pages 26-26)
- Module-specific selectivity: Acute depletion/tagging approaches in human cells showed the eIF3e–eIF3d module selectively promotes translation of membrane/mitochondrial cohorts and that eIF3e is predominantly cytoplasmic, supporting its functional placement at PICs/polysomes. (Duan et al., EMBO J, May 2023; URL: https://doi.org/10.15252/embj.2022112362) (duan2023eif3mrnaselectivity pages 1-2)
- Interface regulation: Biochemical mapping in human cells demonstrated that GIGYF1 binding at the eIF3–eIF4G1 interface displaces eIF3 from eIF4G1, quantitatively repressing initiation on specific transcripts (e.g., innate immune effectors). (Choi et al., Sci Adv, Jul 2024; URL: https://doi.org/10.1126/sciadv.adl5638) (choi2024repressionofmrna pages 1-2)
- Alternative cap binding: Ribosome profiling and biochemical assays showed that under conditions blocking eIF4E1 activity, a subset of mRNAs remains efficiently translated through eIF3d cap-binding, delineating a measurable, eIF3-based alternative initiation route. (Roiuk et al., Nat Commun, Aug 2024; URL: https://doi.org/10.1038/s41467-024-51027-z) (duan2023eif3mrnaselectivity pages 26-26)

Subcellular localization and site of action
- Localization: Endogenous tagging and imaging show eIF3e localizes primarily to the cytoplasm, consistent with roles in cytosolic ribosomes and polysomes. Functional studies place eIF3e at the initiating 43S/48S complexes via the eIF3–eIF4G1 interface. (Duan et al., EMBO J, May 2023; URL: https://doi.org/10.15252/embj.2022112362) (duan2023eif3mrnaselectivity pages 1-2) (Choi et al., Sci Adv, Jul 2024; URL: https://doi.org/10.1126/sciadv.adl5638) (choi2024repressionofmrna pages 1-2)

Pathways and mechanism of action
- Cap-dependent initiation: eIF3e, within the eIF3 complex, participates in bridging eIF4F (via eIF4G1) to the 43S/48S PIC, supporting scanning and start-codon recognition on capped mRNAs. (Choi et al., Sci Adv, 2024; URL: https://doi.org/10.1126/sciadv.adl5638) (choi2024repressionofmrna pages 1-2)
- eIF4E-independent initiation: Under stress or 4E-BP activation, eIF3d’s cap-binding pocket enables cap-dependent but eIF4E-independent initiation; eIF3e’s partnership with eIF3d situates it in this alternative mode. (Roiuk et al., Nat Commun, 2024; URL: https://doi.org/10.1038/s41467-024-51027-z) (duan2023eif3mrnaselectivity pages 26-26)
- Transcript selectivity and early elongation: The eIF3e–eIF3d module confers mRNA selectivity, particularly favoring membrane/mitochondrial protein biogenesis, with evidence for influence on early translational steps. (Duan et al., EMBO J, 2023; URL: https://doi.org/10.15252/embj.2022112362) (duan2023eif3mrnaselectivity pages 1-2)
- Initiation fidelity control: eIF3 core subunits, including eIF3e, restrain near-cognate start site usage, supporting accurate ORF selection. (She et al., Nucleic Acids Res, 2023; URL: https://doi.org/10.1093/nar/gkad329) (duan2023eif3mrnaselectivity pages 26-26)

Clinical and disease relevance (overview from recent studies)
- Cancer-relevant translation programs: Altered eIF3 subunit stoichiometry, including eIF3e depletion, remodels translation of key signaling networks (MAPK), ribosome biogenesis (TOP mRNAs), and stress response mRNAs, illuminating mechanisms by which eIF3 misregulation may contribute to oncogenesis and therapy responses. (Herrmannová et al., eLife, 2024; URL: https://doi.org/10.7554/elife.95846) (herrmannova2024perturbationsineif3 pages 1-2)
- Mitochondrial/membrane proteome support: eIF3e’s partnership with eIF3d to promote translation of mitochondrial and membrane proteins suggests potential links to metabolic reprogramming and tumor cell bioenergetics. (Duan et al., EMBO J, 2023; URL: https://doi.org/10.15252/embj.2022112362) (duan2023eif3mrnaselectivity pages 1-2)

Limitations and open questions
- Nuclear roles and non-translation complexes: While legacy literature has posited connections of “INT6” to other complexes, the 2023–2024 sources analyzed here focus on eIF3e’s role within cytosolic eIF3 at ribosomes and do not provide primary evidence for nuclear or proteasome/CSN functions for human eIF3e. This remains an area for careful, context-specific verification in future work. (duan2023eif3mrnaselectivity pages 1-2, choi2024repressionofmrna pages 1-2, duan2023eif3mrnaselectivity pages 26-26)

Key 2023–2024 sources at a glance
| Citation (first author et al., year) | Journal | Main finding relevant to EIF3E/eIF3 complex | URL | Publication date (month/year) |
|---|---|---|---|---|
| Duan et al., 2023 | EMBO Journal | eIF3e forms a d–e module with eIF3d; selectively promotes translation of membrane/mitochondrial proteins; primarily cytoplasmic localization. (duan2023eif3mrnaselectivity pages 1-2) | https://doi.org/10.15252/embj.2022112362 | May 2023 |
| She et al., 2023 | Nucleic Acids Research | Genome-wide CRISPRi screens: eIF3 core subunits (including eIF3e) regulate start-codon fidelity and translational accuracy. (duan2023eif3mrnaselectivity pages 26-26) | https://doi.org/10.1093/nar/gkad329 | May 2023 |
| Herrmannová et al., 2024 | eLife | Ribo-seq after eIF3e depletion in HeLa: reduced translation of MAPK pathway components, increased TOP mRNA translation, and broad translatome remodeling. (herrmannova2024perturbationsineif3 pages 1-2) | https://doi.org/10.7554/elife.95846 | Nov 2024 |
| Choi et al., 2024 | Science Advances | GIGYF1 binds eIF3 at the eIF3–eIF4G1 interface, disrupting eIF3–eIF4G1 interactions and causing transcript-specific translational repression (mechanistic context implicating peripheral eIF3 subunits such as eIF3e). (choi2024repressionofmrna pages 1-2) | https://doi.org/10.1126/sciadv.adl5638 | Jul 2024 |
| Roiuk et al., 2024 | Nature Communications | eIF4E-independent translation is largely eIF3d-dependent, defining an alternative cap-recognition route involving the eIF3 complex (contextually relevant to eIF3e's role within the complex). (duan2023eif3mrnaselectivity pages 26-26) | https://doi.org/10.1038/s41467-024-51027-z | Aug 2024 |

Table: A concise table of major 2023–2024 studies relating to human EIF3E/eIF3e, including journals, core findings about EIF3E's role in the eIF3 complex and translation, and direct URLs for each publication.

References (URLs and publication dates)
- Duan H et al. eIF3 mRNA selectivity profiling reveals eIF3k as a cancer-relevant regulator of ribosome content. EMBO J. May 2023. URL: https://doi.org/10.15252/embj.2022112362 (supports eIF3e–eIF3d module, cytoplasmic localization, selective translation of membrane/mitochondrial proteins). (duan2023eif3mrnaselectivity pages 1-2)
- She R et al. Translational fidelity screens in mammalian cells reveal eIF3 and eIF4G2 as regulators of start codon selectivity. Nucleic Acids Res. May 2023. URL: https://doi.org/10.1093/nar/gkad329 (supports eIF3 core subunits, including eIF3e, in initiation fidelity). (duan2023eif3mrnaselectivity pages 26-26)
- Herrmannová A et al. Perturbations in eIF3 subunit stoichiometry alter expression of ribosomal proteins and key components of the MAPK signaling pathways. eLife. Nov 2024. URL: https://doi.org/10.7554/elife.95846 (Ribo-seq after eIF3e depletion; MAPK and TOP mRNA effects). (herrmannova2024perturbationsineif3 pages 1-2)
- Choi JH et al. Repression of mRNA translation initiation by GIGYF1 via disrupting the eIF3–eIF4G1 interaction. Sci Adv. Jul 2024. URL: https://doi.org/10.1126/sciadv.adl5638 (mechanistic eIF3–eIF4G1 interface; eIF3 subunits at the bridge). (choi2024repressionofmrna pages 1-2)
- Roiuk M et al. eIF4E-independent translation is largely eIF3d-dependent. Nat Commun. Aug 2024. URL: https://doi.org/10.1038/s41467-024-51027-z (alternative cap recognition via eIF3d; contextual relevance to eIF3e–eIF3d module). (duan2023eif3mrnaselectivity pages 26-26)

References

(duan2023eif3mrnaselectivity pages 26-26): Haoran Duan, Siqiong Zhang, Yoram Zarai, Rupert Öllinger, Yanmeng Wu, Li Sun, Cheng Hu, Yaohui He, Guiyou Tian, Roland Rad, Xiangquan Kong, Yabin Cheng, Tamir Tuller, and Dieter A Wolf. Eif3 mrna selectivity profiling reveals eif3k as a cancer‐relevant regulator of ribosome content. The EMBO Journal, May 2023. URL: https://doi.org/10.15252/embj.2022112362, doi:10.15252/embj.2022112362. This article has 20 citations.
(duan2023eif3mrnaselectivity pages 1-2): Haoran Duan, Siqiong Zhang, Yoram Zarai, Rupert Öllinger, Yanmeng Wu, Li Sun, Cheng Hu, Yaohui He, Guiyou Tian, Roland Rad, Xiangquan Kong, Yabin Cheng, Tamir Tuller, and Dieter A Wolf. Eif3 mrna selectivity profiling reveals eif3k as a cancer‐relevant regulator of ribosome content. The EMBO Journal, May 2023. URL: https://doi.org/10.15252/embj.2022112362, doi:10.15252/embj.2022112362. This article has 20 citations.
(choi2024repressionofmrna pages 1-2): Jung-Hyun Choi, Jun Luo, Geoffrey G. Hesketh, Shuyue Guo, Angelos Pistofidis, Reese Jalal Ladak, Yuxin An, Parisa Naeli, Tommy Alain, T. Martin Schmeing, Anne-Claude Gingras, Thomas Duchaine, Xu Zhang, Nahum Sonenberg, and Seyed Mehdi Jafarnejad. Repression of mrna translation initiation by gigyf1 via disrupting the eif3-eif4g1 interaction. Science Advances, Jul 2024. URL: https://doi.org/10.1126/sciadv.adl5638, doi:10.1126/sciadv.adl5638. This article has 9 citations and is from a highest quality peer-reviewed journal.
(herrmannova2024perturbationsineif3 pages 1-2): Anna Herrmannová, Jan Jelínek, Klára Pospíšilová, Farkas Kerényi, Tomáš Vomastek, Kathleen Watt, Jan Brábek, Mahabub Pasha Mohammad, Susan Wagner, Ivan Topisirovic, and Leoš Shivaya Valášek. Perturbations in eif3 subunit stoichiometry alter expression of ribosomal proteins and key components of the mapk signaling pathways. eLife, Nov 2024. URL: https://doi.org/10.7554/elife.95846, doi:10.7554/elife.95846. This article has 10 citations and is from a domain leading peer-reviewed journal.

Citations

choi2024repressionofmrna pages 1-2
https://doi.org/10.15252/embj.2022112362
https://doi.org/10.1093/nar/gkad329
https://doi.org/10.7554/elife.95846
https://doi.org/10.1126/sciadv.adl5638
https://doi.org/10.1038/s41467-024-51027-z
https://doi.org/10.15252/embj.2022112362,
https://doi.org/10.1126/sciadv.adl5638,
https://doi.org/10.7554/elife.95846,

Perplexity

(EIF3E-deep-research-perplexity.md)

Eukaryotic Translation Initiation Factor 3 Subunit E (EIF3E): Molecular Function, Cellular Roles, and Regulatory Biology Perplexity sonar-deep-research 48 citations 2025-12-12T07:13:14.284484

Eukaryotic Translation Initiation Factor 3 Subunit E (EIF3E): Molecular Function, Cellular Roles, and Regulatory Biology

Eukaryotic translation initiation factor 3 subunit E (EIF3E), also known as INT6 or eIF3-p48, represents a critical non-core component of the multiprotein eIF3 complex that coordinates the initiation of protein synthesis in human cells. While long characterized primarily as a structural component of the translation initiation apparatus, recent research has revealed that EIF3E functions as a specialized regulatory subunit that controls both general and transcript-specific translation through distinct mechanisms, participates in nonsense-mediated mRNA decay pathways, and serves as a hub for coordinating translational control with other cellular processes including mRNA quality surveillance, DNA damage responses, and cell proliferation regulation. The protein occupies a unique functional niche within eIF3, as it is simultaneously essential for global translation initiation when integrated within the complete eIF3 complex, yet plays highly specialized roles in directing the fate of specific mRNAs away from translation toward degradation. EIF3E is found in both cytoplasmic and nuclear compartments where it interacts with distinct molecular partners, and its expression levels are tightly regulated in response to cell cycle progression and stress conditions, with dysregulation associated with multiple human malignancies including breast cancer and colorectal cancer. This comprehensive review synthesizes current molecular understanding of EIF3E structure, biochemistry, and cellular function, establishing it as a multifunctional translation factor whose roles extend far beyond simple recruitment of ribosomes to mRNA.

Molecular Architecture and Structural Organization of EIF3E

The human EIF3E protein, encoded by the EIF3E gene located on chromosome 8, represents a 48 kilodalton polypeptide that serves as a non-core subunit of the eIF3 translation initiation complex[3][27]. As a member of the PCI (proteasome-COP9 signalosome-eIF3) protein family, EIF3E possesses a characteristic PCI domain located within its carboxyl terminus that enables it to interact with other PCI-domain-containing proteins and to participate in the formation of large multiprotein complexes[3][40]. The presence of the PCI domain in EIF3E represents a key structural feature that distinguishes it from the five core subunits of eIF3 (eIF3a, eIF3b, eIF3c, eIF3g, and eIF3i) that are conserved across eukaryotic species from budding yeast to humans[37][40]. The structural organization of EIF3E reveals that this protein integrates into what is termed the PCI/MPN octamer, a shared structural scaffold found not only in eIF3 but also in functionally unrelated complexes such as the 19S proteasome lid and the COP9 signalosome, highlighting an ancient and evolutionarily conserved module for organizing large protein assemblies[3][40].

Within the three-dimensional architecture of the eIF3 complex bound to the 40S ribosomal subunit, EIF3E appears to occupy a position on the solvent-exposed face of the small ribosomal subunit, "sticking out" from the core octameric structure alongside other non-core subunits eIF3h, eIF3k, and eIF3l into the aqueous solution rather than directly contacting the ribosomal surface[8][51]. This positioning suggests that EIF3E, rather than forming direct contacts with ribosomal proteins or RNA, instead serves as an interface for recruiting and stabilizing interactions with additional initiation factors and mRNA regulatory proteins[8][51]. The extended arm-like projections of EIF3E from the main eIF3 body would position this subunit to modulate translation initiation rates in an mRNA-specific manner, potentially by recognizing structural features within mRNA molecules or by serving as a docking site for auxiliary translation factors[8][51]. Recent structural investigations using cryo-electron microscopy and biochemical cross-linking coupled to mass spectrometry have demonstrated that EIF3E integrates into the eIF3 complex through interactions with multiple other subunits, particularly with the large eIF3a-eIF3b-eIF3c core module, though the precise atomic-level interactions remain incompletely characterized due to the high flexibility inherent in this region of eIF3[8].

EIF3E as a Non-Core Component of the eIF3 Translation Initiation Factor

Functional classification of eIF3 subunits into "core" and "non-core" categories emerged from comparative genomic and biochemical analyses demonstrating that while the five core subunits (eIF3a through eIF3i, excluding eIF3d, eIF3e, eIF3f, eIF3h, eIF3k, eIF3l, and eIF3m) are conserved in the simple five-subunit eIF3 complex of budding yeast, the additional eight non-core subunits found in mammalian eIF3 are absent from yeast and appear to regulate rather than to provide essential functions in basic translation initiation[37][40]. EIF3E, classified definitively as a non-core subunit, is notable for being dispensable for the assembly of active eIF3 complexes when reconstituted from recombinant protein subunits in vitro, yet appears essential for eIF3 function in living cells where it plays specialized regulatory roles[37][48]. A landmark biochemical study systematically investigating the minimal requirements for mammalian eIF3 activity demonstrated that a six-subunit complex comprising eIF3a, eIF3b, eIF3c, eIF3e, eIF3f, and eIF3h exhibited robust translation initiation activity, and that removal of any one of these six subunits severely compromised complex assembly and function[37]. These findings established that while eIF3e is not strictly required for in vitro reconstitution of active translation initiation complexes from purified proteins, it is essential for maintaining the integrity and full activity of mammalian eIF3 within intact cells[37].

The functional distinction between core and non-core eIF3 subunits extends beyond simple assembly requirements, as individual non-core subunits including EIF3E have been repeatedly demonstrated to regulate the translation efficiency of specific mRNAs rather than globally affecting protein synthesis rates[14][18]. For example, in studies using the plant model Arabidopsis thaliana, the non-core eIF3h subunit (analogous to mammalian eIF3h) was shown to be dispensable for general protein translation but was required for efficient translation of specific mRNAs containing particular 5' untranslated region sequences, including mRNAs encoding the bZip transcription factor ATB2[14]. This paradigm of selective, mRNA-specific translational control through non-core eIF3 subunits has been documented for human EIF3E, which demonstrates capacity to both activate and repress translation of distinct cellular mRNAs through direct interactions with mRNA secondary structures[18][24]. The discovery that eIF3 subunits including EIF3E possess intrinsic regulatory capacity to control transcriptionally specific translation initiation rates has fundamentally reshaped understanding of eIF3 from a general translation scaffold to a multifunctional regulatory hub capable of selective translational control[18][24][27].

Primary Function of EIF3E within Global Translation Initiation

Translation initiation in eukaryotic cells proceeds through a complex, multi-step pathway involving sequential recruitment and assembly of numerous protein factors with the 40S small ribosomal subunit to form the 43S pre-initiation complex (PIC), which then binds mRNA and scans to locate the initiation codon[3][17][40]. The eIF3 complex, of which EIF3E is a component, serves as an essential scaffold throughout this process, functioning to promote recruitment of multiple initiation factors to the ribosome and to facilitate proper positioning of mRNA within the mRNA binding channel of the 40S subunit[3][8][40]. EIF3E, when present as part of intact eIF3, contributes to these general initiation functions by helping to maintain the structural integrity of the complex and by potentially modulating the conformational flexibility of eIF3 as it undergoes the dramatic rearrangements required to accommodate mRNA binding and start codon recognition[8][51].

The eIF3 complex, including its EIF3E subunit, binds the solvent-exposed face of the 40S ribosomal subunit near the platform region and serves to coordinate the activities of other initiation factors including eIF1, eIF1A, eIF2 (in its GTP-bound ternary complex form), and eIF5[3][8][40]. EIF3E participates in maintaining the open conformation of the 43S PIC that is essential for mRNA entry into the mRNA-binding channel, a function mediated by the concerted action of eIF1 and eIF1A which prevent premature closure of the complex before the correct initiation codon is identified[46]. Additionally, the eIF3 complex including EIF3E is required for the stimulation of scanning of the mRNA along the ribosome from the 5' cap structure to identify the initiator AUG codon, and for the subsequent conformational transition to a closed complex upon AUG recognition[3][8][40]. While EIF3E itself does not directly contact the ribosomal RNA or proteins based on available structural evidence, its presence within the eIF3 complex influences the overall conformational dynamics and positioning of subunits that do make critical contacts with ribosomal components[51].

A striking aspect of EIF3E function is the observation that despite being a non-core subunit, depletion of EIF3E in cultured cells can have significant effects on global translation rates, particularly under certain conditions[53]. Studies examining the consequences of EIF3E knockdown in breast cancer cells revealed modest but reproducible decreases in overall protein synthesis coupled with changes in ribosome occupancy patterns, suggesting that EIF3E contributes to the efficiency of bulk translation initiation even though it is not absolutely required for this process in minimal reconstituted systems[53]. These observations suggest that EIF3E functions as a fine-tuner of general translation initiation capacity in cells, potentially by facilitating the assembly or stability of functional eIF3 complexes, or by optimizing the interaction between eIF3 and other initiation factors or the ribosome itself[37][53].

Specialized Roles of EIF3E in Transcript-Specific Translation Regulation

A paradigm-shifting discovery in the field of translational control has been the revelation that eIF3, rather than functioning simply as a general scaffold for all translation initiation events, selectively binds specific cellular mRNAs and regulates their translation through direct interactions with mRNA secondary structures[18]. These studies employing photo-activatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) identified a limited set of mRNAs, comprising only approximately three percent of total expressed transcripts, that crosslink directly with eIF3 subunits within living cells[18]. Remarkably, eIF3 acts as both a translation activator and repressor of different mRNAs, a dual functional capacity that was definitively demonstrated through analysis of the proto-oncogene c-Jun and the tumor suppressor BTG1[18].

For the c-Jun mRNA, eIF3 binding to a conserved hairpin stem-loop structure located within the 5' untranslated region directly promotes translation initiation through a cap-dependent mechanism requiring the 5' methyl-guanosine cap, yet this eIF3-mediated activation occurs independently of the canonical eIF4F cap-binding complex that typically initiates cap-dependent translation[18][24]. The stem-loop structure within the c-Jun 5' UTR that recruits eIF3 has been structurally characterized by nuclear magnetic resonance spectroscopy, revealing a complex three-dimensional architecture that exhibits similarities to internal ribosomal entry sites (IRES) elements from hepatitis C virus, suggesting mechanistic parallels between viral cap-independent translation and specialized eIF3-mediated translation of cellular proto-oncogenes[24]. EIF3E likely contributes to this specialized translation mechanism through its position within the eIF3 complex and potential interactions with the mRNA stem-loop structure, though the precise atomic contacts between EIF3E and specific mRNA bases remain to be determined[24].

In contrast to its role in promoting c-Jun translation, eIF3 binding to a stem-loop structure within the BTG1 mRNA (B cell translocation gene 1, a tumor suppressor) suppresses translation of this transcript[18]. The structural determinants that cause the identical eIF3 complex to activate translation of one mRNA while repressing another remain incompletely understood, though evidence suggests that the surrounding mRNA sequence context, as well as the identity of additional trans-acting factors present in the cellular milieu, influences whether eIF3 binding results in translational activation or repression[18]. These observations establish that EIF3E, as a component of the eIF3 complex that directly contacts target mRNAs, must be capable of recognizing distinct molecular features that discriminate between activation and repression targets, and of transducing this recognition into appropriate regulatory outcomes[18].

A second major discovery regarding eIF3-mediated transcript-specific translation involves recognition of N6-methyladenosine (m6A) modifications within the 5' untranslated regions of specific mRNAs[31][32]. eIF3 directly binds m6A residues in particular sequence contexts within 5' UTRs and recruits the 43S pre-initiation complex to these mRNAs to initiate translation in a manner that is independent of the canonical 5' methylguanosine cap and the eIF4F cap-binding complex[31][32]. This m6A-dependent translation becomes particularly important during cellular stress conditions such as heat shock or endoplasmic reticulum stress, when cap-dependent translation is inhibited yet certain stress-response genes including heat shock protein 70 (HSP70) must continue to be translated to allow cellular adaptation[31]. EIF3E presumably participates in m6A recognition and recruitment of the translation machinery, though specific evidence establishing EIF3E's direct role in m6A-mediated translation initiation remains to be reported[31].

A remarkable additional finding has revealed that eIF3, contrary to its well-established association with 5' cap-proximal regions of mRNA, also engages extensively with the 3' untranslated region terminals of actively translated mRNAs[15]. Using Quick-irCLIP (rapid infrared crosslinking and immunoprecipitation) and alternative polyadenylation sequencing technologies, researchers demonstrated that eIF3 crosslinks predominantly to the 3' UTR termini of multiple mRNA isoforms, adjacent to the poly(A) tail, and that this 3' UTR engagement correlates with the overall translation efficiency of those transcripts[15]. Furthermore, eIF3 shows preference for specific 3' UTR isoforms produced through alternative polyadenylation, with evidence suggesting that 3' UTR binding by eIF3 reflects the initiation factor's involvement in mRNA circularization, a process in which the 5' and 3' ends of mRNA are brought into close proximity by protein bridges including eIF4G and poly(A)-binding protein[15]. This function of eIF3 including EIF3E in mRNA circularization likely represents a general mechanism for enhancing translation initiation by stabilizing interactions between the 5' cap-binding machinery and the translation machinery recruited to initiate protein synthesis[15].

Nonsense-Mediated Decay and the Specialized Role of EIF3E in mRNA Surveillance

One of the most extensively characterized specialized functions of EIF3E is its essential role in nonsense-mediated mRNA decay (NMD), a quality control pathway that recognizes and degrades mRNAs containing premature termination codons (PTCs)[2][7][10][26][49]. NMD functions to prevent accumulation of truncated, potentially toxic proteins by detecting mRNAs in which translation termination occurs upstream of exon-exon junctions generated during pre-mRNA splicing, with a threshold of approximately 50-55 nucleotides upstream of the downstream-most exon junction typically triggering degradation[26][49]. The molecular recognition of NMD substrates requires a "pioneer" round of translation during which newly synthesized mRNAs, still bound by the nuclear cap-binding heterodimer CBP80-CBP20 (as opposed to the canonical translation cap-binding protein eIF4E), are subjected to translation initiation in the nucleus where interaction between translation termination factors and the exon junction complex machinery results in recruitment of the UPF proteins that execute NMD[26][49][52].

Detailed biochemical studies have demonstrated that EIF3E (also designated INT6) is uniquely required specifically for the pioneer round of translation and subsequent NMD, while the core eIF3b subunit is required for both pioneer round translation and steady-state translation[26][49]. RNA interference-mediated knockdown of EIF3E expression strongly inhibits NMD of model substrates carrying premature stop codons without affecting the stability of normal mRNAs or the global translation rate, establishing EIF3E as a specialized component of the NMD machinery[2][7][10]. Mechanistically, immunoprecipitation experiments have demonstrated that EIF3E co-purifies with CBP80, the nuclear cap-binding protein, and with UPF2, a core component of the NMD machinery[26][49]. These interactions suggest a model in which EIF3E, in association with eIF3, facilitates the recruitment of mRNA to the CBP80-bound initiation complex and, in conjunction with UPF2, directs these newly synthesized mRNAs toward the NMD pathway rather than toward continuing translation[26][49].

The mechanistic basis for EIF3E's selective role in NMD versus general translation appears to involve its interaction with specific binding partners that are present in the nuclear compartment but not in the cytoplasm. EIF3E possesses sequences consistent with nuclear localization signals and nuclear export signals, enabling it to shuttle between the nucleus and cytoplasm[38]. Evidence demonstrates that EIF3E interacts with the MIF4G (middle domain of eIF4G-1) motifs found in various protein partners, raising the possibility that EIF3E specifically binds to distinct versions of eIF3 complexes that associate with UPF2 and the CBP80 cap-binding protein in the nuclear compartment[26][49]. The composition of eIF3 complexes appears to be dynamic, with EIF3E-containing complexes potentially being enriched in the nucleus where they participate in the pioneer round of translation and NMD, while EIF3 complexes lacking EIF3E or containing different complements of non-core subunits mediate steady-state translation in the cytoplasm[26][38].

The functional significance of the EIF3E-dependent NMD pathway extends beyond simple quality control, as numerous transcripts are known to be regulated by NMD in response to cellular conditions, making EIF3E a critical node in pathways controlling cellular protein composition[26]. Furthermore, disruption of NMD through EIF3E knockdown has been shown to lead to accumulation of PTC-containing transcripts from genes including those encoding proteins involved in cell cycle regulation and apoptosis, suggesting that dysregulation of the EIF3E-dependent NMD pathway could contribute to malignant transformation through altered expression of cell cycle control proteins[26].

Cellular Localization and Subcellular Compartmentalization of EIF3E

In contrast to other eIF3 subunits which localize predominantly to the cytoplasm where translation initiation occurs, EIF3E exhibits a striking and partially nuclear localization pattern that has been revealed through immunofluorescence microscopy using specific antibodies[38]. Quantitative cell fractionation studies have confirmed that EIF3E is present in both nuclear and cytoplasmic fractions, distinguishing it from the bulk of the eIF3 complex which resides in the cytoplasm[38]. The nuclear pool of EIF3E has been observed to accumulate in PML bodies, nuclear foci associated with various regulatory functions including DNA damage response and protein ubiquitination[38]. Notably, the extent of nuclear localization of EIF3E varies with cell cycle position, with particularly striking decreases in nuclear EIF3E fluorescence occurring during early S phase in primary human fibroblasts, suggesting that the subcellular distribution of EIF3E is subject to active, cell cycle-regulated redistribution[38].

The presence of nuclear EIF3E likely reflects its participation in the pioneer round of translation and NMD pathway, processes that occur predominantly in the nucleus for newly synthesized mRNAs still bound by CBP80[38]. The partial nuclear localization of EIF3E, in contrast to the predominantly cytoplasmic localization of other eIF3 subunits, indicates that EIF3E may represent a dedicated component that is selectively recruited to nuclear pioneer round translation complexes and subsequently removed or sequestered to prevent its participation in cytoplasmic steady-state translation[38]. The mechanism of nuclear-cytoplasmic shuttling of EIF3E remains incompletely characterized, though its possession of putative nuclear localization signals and nuclear export sequences is consistent with active transport mechanisms involving importins and exportins[38].

The cell cycle-dependent redistribution of EIF3E from nuclear to cytoplasmic locales during S phase raises intriguing questions about the biological function driving this redistribution[38]. One possibility is that decreased nuclear EIF3E during S phase reflects a need for its relocation to the cytoplasm to support increased translation of S-phase-specific proteins required for DNA replication[38]. Alternatively, the redistribution might reflect altered requirements for pioneer round translation or NMD during DNA replication, or might be secondary to changes in eIF3 complex composition that occur during different cell cycle phases[38]. Understanding the mechanisms and functional consequences of EIF3E shuttling represents an important area for future research.

Post-Translational Modification and Regulatory Protein Interactions of EIF3E

The activity of EIF3E is subject to regulation through post-translational modifications including phosphorylation, though the complete repertoire of EIF3E modification sites and their functional consequences remain incompletely defined[39][42]. Phosphorylation by DNA-damage-responsive kinases, likely including ATM and ATR family members, has been reported to occur on EIF3E following DNA damage[39]. Additionally, EIF3E is phosphorylated as a consequence of mTOR signaling pathway activation, with particular relevance to the translational control function of eIF3[39]. The eIF3 complex serves as a hub for cellular signaling through the mTOR-S6K1 axis, with activated mTOR/Raptor binding to eIF3 and phosphorylating ribosomal S6 kinase 1 (S6K1) to promote its release from the complex and subsequent phosphorylation of downstream targets including eIF4B[3]. EIF3E, as a component of eIF3, participates in this signaling function, though whether EIF3E itself serves as a direct substrate for mTOR or S6K1 remains to be definitively established[39].

EIF3E interacts with multiple other cellular proteins beyond its integrated associations within the eIF3 complex. Notably, EIF3E has been demonstrated to interact with UPF2, a core component of the NMD machinery, and with CBP80, the nuclear cap-binding protein[26][49]. These interactions likely represent the molecular basis for EIF3E's specialized function in the NMD pathway and pioneer round translation[26][49]. Additionally, EIF3E has been shown to interact with subunits of the COP9 signalosome, a multiprotein complex involved in regulating protein ubiquitination and neddylation, suggesting potential cross-talk between translation initiation and post-translational protein modification pathways[38]. In fission yeast, the INT6 ortholog has been demonstrated to interact with the 26S proteasome and to promote proteasome assembly through interaction with the Rpn5 regulatory particle subunit[28], though analogous proteasome interactions for human EIF3E remain to be characterized[28].

The regulation of EIF3E protein levels itself appears to be subject to control through multiple mechanisms. Several studies have reported that EIF3E expression is downregulated in various human malignancies, including breast cancer and colorectal cancer[9][50], raising questions about mechanisms controlling EIF3E protein stability or synthesis. Whether EIF3E undergoes proteasomal degradation, is subject to microRNA-mediated translational repression, or is simply downregulated at the transcriptional level in cancer cells remains incompletely understood and represents an important question for future investigation[9][50].

Functional Roles of EIF3E in Stress Responses and Cellular Adaptation

During cellular stress conditions that compromise cap-dependent translation, eIF3 including EIF3E plays enhanced roles in promoting alternative cap-independent translation mechanisms that sustain synthesis of critical stress-response proteins[31][32][34]. Heat stress, for example, triggers a global shutdown of cap-dependent translation while selectively maintaining or even increasing translation of heat shock proteins, a switching process that involves m6A-dependent eIF3-mediated translation initiation[31][34]. EIF3E participates in this stress-adaptive function as a component of eIF3, enabling continued translation of mRNAs marked with m6A modifications within their 5' UTRs[31][32]. Additionally, EIF3E undergoes relocalization into cytoplasmic foci in response to heat stress and osmotic stress, implicating it in stress granule assembly or modification, though the precise functional consequences of this relocalization remain to be elucidated[41].

The capacity of EIF3E to support stress-responsive translation appears to extend to viral infection responses, as eIF3 including EIF3E is required for the initiation of translation from internal ribosomal entry sites (IRES) of many RNA viruses[55][58]. Hepatitis C virus (HCV), for example, depends critically upon eIF3-mediated recruitment of the translation machinery to its IRES-containing RNA genome, and the interaction between eIF3 and the HCV IRES has been extensively characterized structurally[55][58]. The requirement for EIF3E in viral IRES-mediated translation likely reflects its general function within the eIF3 complex in promoting translation from structured mRNA elements, a capacity that is exploited by viruses but is also employed for cellular mRNAs in stress situations[55][58].

Role of EIF3E in Cancer and Dysregulation in Human Malignancies

The involvement of EIF3E in human cancer has been established through multiple independent lines of evidence demonstrating that EIF3E expression is frequently altered in diverse malignancies, and that changes in EIF3E abundance influence tumor cell biology in important ways[9][22][27][50][53][57]. The role of EIF3E in cancer is complex and, in certain respects, paradoxical, with evidence supporting both tumor suppressor and oncogenic functions depending on the cellular context and cancer type.

In breast cancer, reduced expression of EIF3E/INT6 has been documented in up to 37 percent of cases, making it one of the most frequently downregulated eIF3 subunits in this disease[9][19][57]. Expression of a truncated mutant version of the murine eIF3e/INT6 protein leads to malignant transformation of normal mammary cells, providing evidence that loss of full-length EIF3E function promotes breast oncogenesis[9][19][57]. However, these tumor suppressor findings initially conflicted with an earlier study reporting that reduction of EIF3E expression in certain breast cancer cell lines led to decreased translation of specific oncogenes, suggesting a potential oncogenic role for EIF3E[22]. This apparent paradox has been partially reconciled through investigations revealing that EIF3E plays cell-context-dependent roles: decreased EIF3E expression causes breast epithelial cells to undergo epithelial-to-mesenchymal transition (EMT), imparting invasive and migratory properties while also increasing expression of key EMT regulators including SNAIL1 and ZEB2[9][19][57]. These findings suggest that EIF3E functions as a tumor suppressor by preventing the EMT process and maintaining epithelial cell characteristics, with loss of EIF3E promoting metastatic capability in breast cancer[9][19][57].

In colorectal cancer, high EIF3E expression has been associated with poor prognosis and increased tumor aggressiveness[50]. Multivariate analysis of colorectal cancer patients revealed that elevated EIF3E expression independently predicted both reduced overall survival and reduced disease-free survival[50]. Mechanistic studies in colon cancer cell lines demonstrated that knockdown of EIF3E inhibited cell proliferation, reduced colony formation, and promoted apoptosis, supporting an oncogenic role for EIF3E in this cancer type[50]. These findings suggest that the functional role of EIF3E in cancer biology is cancer-type-specific, with EIF3E serving as a tumor suppressor in breast cancer but as an oncogene in colorectal cancer[9][50]. The basis for this context-dependent function may reside in the specialized mRNAs that EIF3E regulates in different cell types; EIF3E's capacity to selectively control translation of specific cell proliferation and apoptosis-regulating mRNAs could result in differing net effects on tumor progression depending on which target mRNAs dominate in particular cancer types[18][50].

Recent investigations have revealed additional mechanisms linking EIF3E to cancer biology and therapeutic responses. In EIF3E-depleted breast cancer cells, reduced synthesis of PARP1 (poly-ADP-ribose polymerase 1) protein occurs due to weakened translation of the corresponding mRNA, resulting in decreased cellular ability to synthesize poly(ADP-ribose) polymers and rendering these cells resistant to PARP inhibitor drugs[53]. Additionally, EIF3E depletion leads to impaired DNA repair via homologous recombination, suggesting that EIF3E may regulate translation of mRNAs encoding proteins critical for DNA damage responses[53]. Paradoxically, the DNA repair defect resulting from EIF3E loss renders cells vulnerable to replication stress, and EIF3E-depleted breast cancer cells undergo premature senescence with activation of senescence-associated secretory phenotype (SASP) characterized by increased production of inflammatory cytokines including IL-6, IL-8, and CXCL1[53]. These findings reveal an unexpected tumor suppressor function for EIF3E in maintaining genomic stability, contrasting with its role in suppressing EMT, and suggesting that multiple cellular processes depend upon EIF3E-regulated translation for proper function[53].

Specialized Translation Initiation Mechanisms Involving EIF3E

Beyond its roles in general translation initiation and NMD, EIF3E participates in additional specialized translation initiation mechanisms that represent important regulatory pathways in eukaryotic cells. One such mechanism involves the recognition of upstream open reading frames (uORFs) present in the 5' untranslated regions of certain cellular mRNAs. Following translation of a short upstream ORF and termination at its stop codon, eIF3 can remain bound to the ribosome through elongation and termination events to promote reinitiation at downstream ORFs, a process termed reinitiation[3][40][46]. EIF3E likely participates in reinitiation through its functions in maintaining eIF3 complex stability and in facilitating conformational changes of the ribosomal complex required to resume scanning for the next AUG codon[46]. The classic example of reinitiation-mediated translational control involves the GCN4 transcription factor, whose translation is regulated by uORFs in response to amino acid starvation through mechanisms dependent on eIF3[44][46].

Another specialized mechanism involves programmed stop codon readthrough, a process in which translation termination factors are prevented from recognizing stop codons, allowing translation to proceed through the stop codon and into normally untranslated downstream sequences[3][40]. eIF3 has been implicated in regulating programmed readthrough in yeast through interactions with pre-termination complexes, and EIF3E may similarly participate in this process in mammalian cells, though direct evidence specific to EIF3E remains to be reported[3][40]. Additionally, eIF3 including EIF3E plays roles in recycling of ribosomes following translation termination, promoting the dissociation of 40S and 60S subunits and preventing premature rejoining, ensuring that ribosomes are properly released for participation in subsequent rounds of translation initiation[3][13][40]. These diverse specialized functions of EIF3E highlight its critical role not only in initiating translation but in coordinating multiple steps throughout the entire translation cycle.

Concluding Synthesis and Future Perspectives

EIF3E (eukaryotic translation initiation factor 3 subunit E), also designated INT6 or eIF3-p48, emerges from current scientific understanding as a multifunctional translation factor whose roles extend far beyond a simple structural role within the eIF3 translation initiation complex. As a non-core component of eIF3, EIF3E contributes to the general capacity of cells to initiate translation on most cellular mRNAs while simultaneously serving as a dedicated regulatory subunit capable of selectively controlling the translation of specific transcripts that encode cell proliferation and apoptosis regulators. The specialized functions of EIF3E in transcript-specific translational control derive from its participation in eIF3-mRNA interactions that are mediated by mRNA secondary structures and post-transcriptional modifications such as m6A methylation, mechanisms that enable EIF3E to discriminate between different mRNA substrates and to impose appropriate regulatory decisions upon them.

The unique role of EIF3E in the nuclear pioneer round of translation and in the nonsense-mediated mRNA decay pathway represents a critical quality control function that prevents accumulation of truncated protein products that might otherwise exert dominant-negative effects on cellular function. The regulated subcellular localization of EIF3E, with partial nuclear sequestration that varies with cell cycle position, supports the hypothesis that EIF3E represents a specialized eIF3 component dedicated to nuclear mRNA surveillance functions. The dysregulation of EIF3E expression in human malignancies, with a complex pattern of tumor-suppressive functions in breast cancer and oncogenic roles in colorectal cancer, underscores the fundamental importance of balanced EIF3E expression for proper cellular behavior and suggests potential therapeutic strategies targeting EIF3E-mediated translation control in cancer treatment.

Future research into EIF3E biology should prioritize several important questions. First, the atomic-level structural characterization of EIF3E within intact eIF3 complexes and in association with ribosomes and mRNA remains incomplete, with high-resolution cryo-EM structures providing detailed visualization of EIF3E's exact role in eIF3-ribosome positioning and conformational dynamics. Second, the complete identification of cellular mRNAs whose translation is specifically regulated by EIF3E, and the characterization of the sequence and structural determinants that distinguish EIF3E-activated versus EIF3E-repressed mRNAs, would provide critical insights into the mechanisms of selective translational control. Third, the mechanisms controlling EIF3E expression and subcellular localization, and the identity of trans-acting factors that recruit EIF3E to specific cellular compartments and protein complexes, represent important areas for investigation. Fourth, the therapeutic potential of modulating EIF3E expression or function as a strategy for treating cancers and other diseases characterized by dysregulated protein synthesis requires further exploration through both basic research and preclinical development studies.

Citations

https://www.ncbi.nlm.nih.gov/gene/3646
https://pubmed.ncbi.nlm.nih.gov/17468741/
https://en.wikipedia.org/wiki/Eukaryotic_initiation_factor_3
https://www.uniprot.org/uniprotkb/P60228/entry
https://www.proteinatlas.org/ENSG00000104408-EIF3E
https://royalsocietypublishing.org/rstb/article/372/1716/20160176/23133/Human-eIF3-from-blobology-to-biological
https://pmc.ncbi.nlm.nih.gov/articles/PMC2002529/
https://academic.oup.com/nar/article/45/19/10948/4157872
https://pubmed.ncbi.nlm.nih.gov/22907435/
https://pmc.ncbi.nlm.nih.gov/articles/PMC3973348/
https://article.imrpress.com/bri/Landmark/articles/pdf/Landmark4469.pdf
https://www.abcam.com/en-us/targets/eif3e/19755
https://pmc.ncbi.nlm.nih.gov/articles/PMC535877/
https://elifesciences.org/articles/102977
https://pmc.ncbi.nlm.nih.gov/articles/PMC4003276/
https://www.nature.com/articles/nrm1488
https://pmc.ncbi.nlm.nih.gov/articles/PMC4603833/
https://pmc.ncbi.nlm.nih.gov/articles/PMC3089590/
https://pmc.ncbi.nlm.nih.gov/articles/PMC5820134/
https://pubmed.ncbi.nlm.nih.gov/20453879/
https://pmc.ncbi.nlm.nih.gov/articles/PMC7225069/
https://pmc.ncbi.nlm.nih.gov/articles/PMC2494926/
https://www.embopress.org/doi/10.1038/sj.embor.7400955
https://www.genecards.org/cgi-bin/carddisp.pl?gene=EIF3E
https://pmc.ncbi.nlm.nih.gov/articles/PMC111132/
https://www.uniprot.org/uniprot/A0A2T3A300
https://www.proteinatlas.org/ENSG00000104408-EIF3E/structure
https://pmc.ncbi.nlm.nih.gov/articles/PMC7333474/
https://pmc.ncbi.nlm.nih.gov/articles/PMC4695625/
https://pmc.ncbi.nlm.nih.gov/articles/PMC1173091/
https://royalsocietypublishing.org/rsos/article/12/7/250132/235434/Translational-reprogramming-under-heat-stress-a
https://pmc.ncbi.nlm.nih.gov/articles/PMC8036370/
https://pmc.ncbi.nlm.nih.gov/articles/PMC1933396/
https://pmc.ncbi.nlm.nih.gov/articles/PMC6495725/
https://www.uniprot.org/uniprot/Q3UIG0
https://pmc.ncbi.nlm.nih.gov/articles/PMC2666973/
https://academic.oup.com/nar/article/47/15/8282/5530675
https://pmc.ncbi.nlm.nih.gov/articles/PMC2950517/
https://pmc.ncbi.nlm.nih.gov/articles/PMC5311491/
https://elifesciences.org/articles/20934
https://academic.oup.com/g3journal/article/2/11/1393/6026000
https://pmc.ncbi.nlm.nih.gov/articles/PMC4230162/
https://pmc.ncbi.nlm.nih.gov/articles/PMC4193665/
https://pmc.ncbi.nlm.nih.gov/articles/PMC8021025/
https://www.pnas.org/doi/10.1073/pnas.2505538122
https://pmc.ncbi.nlm.nih.gov/articles/PMC4151992/
https://pmc.ncbi.nlm.nih.gov/articles/PMC6884710/
https://www.nature.com/articles/s43018-024-00839-5

📄 View Raw YAML

id: P60228
gene_symbol: EIF3E
product_type: PROTEIN
status: COMPLETE
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: EIF3E (also known as INT6 or eIF3-p48) encodes eukaryotic
  translation initiation factor 3 subunit E, a 48 kDa PCI domain-containing
  non-core subunit of the eIF3 complex. EIF3E forms part of module C of eIF3
  together with EIF3C, EIF3D, EIF3K and EIF3L. It functions as a structural
  component of eIF3 that bridges cap-recognition machinery to the 43S/48S
  pre-initiation complex, supporting mRNA-selective translation initiation.
  EIF3E partners with EIF3D to form a functional d-e module that promotes
  selective translation of membrane-associated and mitochondrial protein mRNAs.
  Additionally, EIF3E plays a specialized role in nonsense-mediated mRNA decay
  (NMD), participating in the pioneer round of translation through interactions
  with the nuclear cap-binding protein CBP80 and the NMD factor UPF2. The
  protein localizes to both cytoplasm and nucleus, with nuclear localization in
  PML bodies that varies with cell cycle phase. EIF3E contributes to start codon
  fidelity and controls translation of specific mRNA cohorts including MAPK
  pathway components and TOP mRNAs encoding ribosomal proteins.
existing_annotations:
  - term:
      id: GO:0005852
      label: eukaryotic translation initiation factor 3 complex
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EIF3E is a well-established component of the eIF3 complex.
        Multiple structural and biochemical studies confirm its membership in
        eIF3, where it forms part of module C together with EIF3C, EIF3D, EIF3K
        and EIF3L. Mass spectrometry and structural studies have characterized
        the eIF3 complex extensively.
      action: ACCEPT
      reason: Core annotation. EIF3E membership in the eIF3 complex is
        definitively established through multiple lines of evidence including
        mass spectrometry characterization, cryo-EM structures, and biochemical
        reconstitution. The IBA annotation is fully supported by experimental
        data from multiple laboratories.
      supported_by:
        - reference_id: PMID:17322308
          supporting_text: Structural characterization of the human eukaryotic
            initiation factor 3 protein complex by mass spectrometry
        - reference_id: PMID:18599441
          supporting_text: Mass spectrometry reveals modularity and a complete
            subunit interaction map of the eukaryotic translation factor eIF3
        - reference_id: PMID:17581632
          supporting_text: Reconstitution reveals the functional core of
            mammalian eIF3
        - reference_id: file:human/EIF3E/EIF3E-deep-research-perplexity.md
          supporting_text: See deep research file for comprehensive analysis
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EIF3E exhibits dual localization in cytoplasm and nucleus. The
        protein contains nuclear localization and export signals enabling
        shuttling between compartments. Nuclear EIF3E accumulates in PML bodies
        and participates in pioneer round translation and NMD in the nuclear
        compartment.
      action: ACCEPT
      reason: Nuclear localization of EIF3E has been demonstrated by
        immunofluorescence microscopy and cell fractionation studies. The
        nuclear pool is functionally important for pioneer round translation and
        NMD. The annotation is supported by phylogenetic analysis and
        experimental data.
      supported_by:
        - reference_id: PMID:10504338
          supporting_text: Interaction between the Ret finger protein and the
            Int-6 gene product and co-localisation into nuclear bodies
        - reference_id: PMID:17468741
          supporting_text: Human INT6/eIF3e is required for nonsense-mediated
            mRNA decay
  - term:
      id: GO:0006413
      label: translational initiation
    evidence_type: IBA
    original_reference_id: GO_REF:0000033
    review:
      summary: EIF3E is a component of eIF3 which is essential for translation
        initiation. The eIF3 complex associates with the 40S ribosomal subunit
        and facilitates recruitment of eIF-1, eIF-1A, eIF-2:GTP:methionyl-tRNAi
        and eIF-5 to form the 43S pre-initiation complex. EIF3 also stimulates
        mRNA recruitment and scanning for AUG recognition.
      action: ACCEPT
      reason: Translational initiation is the core function of the eIF3 complex.
        EIF3E as a component contributes to this function. Multiple
        reconstitution and functional studies confirm this role.
      supported_by:
        - reference_id: PMID:17581632
          supporting_text: Reconstitution reveals the functional core of
            mammalian eIF3
        - reference_id: PMID:25849773
          supporting_text: eIF3 targets cell-proliferation messenger RNAs for
            translational activation or repression
  - term:
      id: GO:0001732
      label: formation of cytoplasmic translation initiation complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000104
    review:
      summary: EIF3E participates in formation of translation initiation
        complexes as part of eIF3. The eIF3 complex bridges cap-binding
        machinery to the 43S/48S pre-initiation complex.
      action: ACCEPT
      reason: This annotation correctly reflects EIF3E's role as a component of
        eIF3 in forming translation initiation complexes. The IEA annotation
        based on UniRule is consistent with experimental evidence.
      supported_by:
        - reference_id: PMID:16920360
          supporting_text: 'eIF3: a versatile scaffold for translation initiation
            complexes'
  - term:
      id: GO:0002183
      label: cytoplasmic translational initiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000104
    review:
      summary: EIF3E functions in cytoplasmic translation initiation as part of
        the eIF3 complex. However, EIF3E also participates in nuclear pioneer
        round translation.
      action: ACCEPT
      reason: Cytoplasmic translational initiation is a core function of eIF3.
        While EIF3E also has nuclear roles, its participation in cytoplasmic
        translation initiation is well established.
      supported_by:
        - reference_id: PMID:17581632
          supporting_text: Reconstitution reveals the functional core of
            mammalian eIF3
  - term:
      id: GO:0003743
      label: translation initiation factor activity
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: EIF3E contributes to translation initiation factor activity as a
        component of the eIF3 complex. The eIF3 complex is essential for
        multiple steps in translation initiation.
      action: ACCEPT
      reason: Translation initiation factor activity is the core molecular
        function of eIF3. EIF3E contributes to this activity as a subunit of the
        complex. The annotation uses appropriate qualifier "contributes_to" in
        primary annotations.
      supported_by:
        - reference_id: PMID:17581632
          supporting_text: Reconstitution reveals the functional core of
            mammalian eIF3
        - reference_id: PMID:25849773
          supporting_text: eIF3 targets cell-proliferation messenger RNAs for
            translational activation or repression
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IEA
    original_reference_id: GO_REF:0000104
    review:
      summary: Nuclear localization of EIF3E is supported by multiple
        experimental studies showing shuttling between cytoplasm and nucleus,
        with accumulation in PML bodies.
      action: ACCEPT
      reason: Duplicate of IBA annotation for nucleus. Both are valid as nuclear
        localization is experimentally confirmed.
      supported_by:
        - reference_id: PMID:10504338
          supporting_text: Interaction between the Ret finger protein and the
            Int-6 gene product and co-localisation into nuclear bodies
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: EIF3E localizes predominantly to the cytoplasm where it functions
        in translation initiation as part of the eIF3 complex at ribosomes and
        polysomes.
      action: ACCEPT
      reason: Cytoplasmic localization is well established for EIF3E where it
        carries out its primary function in translation initiation. Endogenous
        tagging confirms predominantly cytoplasmic localization.
      supported_by:
        - reference_id: PMID:10504338
          supporting_text: Interaction between the Ret finger protein and the
            Int-6 gene product and co-localisation into nuclear bodies
  - term:
      id: GO:0005852
      label: eukaryotic translation initiation factor 3 complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Duplicate annotation for eIF3 complex membership. EIF3E is a
        well-characterized component of the 13-subunit human eIF3 complex.
      action: ACCEPT
      reason: Redundant with IBA annotation but correct. EIF3E membership in
        eIF3 is definitively established.
      supported_by:
        - reference_id: PMID:18599441
          supporting_text: Mass spectrometry reveals modularity and a complete
            subunit interaction map of the eukaryotic translation factor eIF3
  - term:
      id: GO:0006412
      label: translation
    evidence_type: IEA
    original_reference_id: GO_REF:0000043
    review:
      summary: EIF3E is involved in translation through its role in translation
        initiation. The annotation to the general term "translation" is correct
        but less informative than specific initiation annotations.
      action: ACCEPT
      reason: This general annotation is correct but less specific than the
        translational initiation annotations. It captures the broader biological
        process involvement correctly.
      supported_by:
        - reference_id: PMID:17581632
          supporting_text: Reconstitution reveals the functional core of
            mammalian eIF3
  - term:
      id: GO:0006413
      label: translational initiation
    evidence_type: IEA
    original_reference_id: GO_REF:0000120
    review:
      summary: Duplicate annotation for translational initiation. This is a core
        function of EIF3E as part of the eIF3 complex.
      action: ACCEPT
      reason: Redundant with IBA annotation but correct. Translational
        initiation is a core function.
      supported_by:
        - reference_id: PMID:17581632
          supporting_text: Reconstitution reveals the functional core of
            mammalian eIF3
  - term:
      id: GO:0016282
      label: eukaryotic 43S preinitiation complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000104
    review:
      summary: EIF3E as part of eIF3 is a component of the 43S preinitiation
        complex. The eIF3 complex facilitates assembly of the 43S PIC containing
        the 40S ribosomal subunit, eIF1, eIF1A, and eIF2-GTP-Met-tRNAi ternary
        complex.
      action: ACCEPT
      reason: EIF3 is a core component of the 43S preinitiation complex. This
        annotation correctly reflects EIF3E's participation in this complex as
        an eIF3 subunit.
      supported_by:
        - reference_id: PMID:16920360
          supporting_text: 'eIF3: a versatile scaffold for translation initiation
            complexes'
  - term:
      id: GO:0016605
      label: PML body
    evidence_type: IEA
    original_reference_id: GO_REF:0000044
    review:
      summary: EIF3E localizes to PML nuclear bodies. Immunofluorescence
        microscopy demonstrates co-localization of EIF3E with PML bodies in the
        nucleus.
      action: ACCEPT
      reason: PML body localization of EIF3E is experimentally confirmed by
        immunofluorescence microscopy. The nuclear pool of EIF3E accumulates in
        PML bodies.
      supported_by:
        - reference_id: PMID:10504338
          supporting_text: Interaction between the Ret finger protein and the
            Int-6 gene product and co-localisation into nuclear bodies
  - term:
      id: GO:0032991
      label: protein-containing complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000117
    review:
      summary: EIF3E is part of protein-containing complexes including the eIF3
        complex. However, this is too general an annotation when more specific
        complex annotations exist.
      action: MARK_AS_OVER_ANNOTATED
      reason: While technically correct, this annotation is too general when
        more specific annotations (eIF3 complex, 43S/48S preinitiation
        complexes) exist. The specific complex annotations provide more
        informative functional context.
  - term:
      id: GO:0033290
      label: eukaryotic 48S preinitiation complex
    evidence_type: IEA
    original_reference_id: GO_REF:0000104
    review:
      summary: EIF3E as part of eIF3 is a component of the 48S preinitiation
        complex, formed when the 43S PIC binds mRNA and scans to find the start
        codon.
      action: ACCEPT
      reason: EIF3 is a component of the 48S preinitiation complex. This
        annotation correctly reflects EIF3E's participation in this complex as
        an eIF3 subunit.
      supported_by:
        - reference_id: PMID:16920360
          supporting_text: 'eIF3: a versatile scaffold for translation initiation
            complexes'
  - term:
      id: GO:0071540
      label: eukaryotic translation initiation factor 3 complex, eIF3e
    evidence_type: IEA
    original_reference_id: GO_REF:0000104
    review:
      summary: This annotation indicates EIF3E is specifically the eIF3e subunit
        of the eIF3 complex. This is a highly specific cellular component
        annotation.
      action: ACCEPT
      reason: EIF3E encodes the eIF3e subunit. This specific annotation
        correctly identifies its position within the eIF3 complex.
  - term:
      id: GO:0014069
      label: postsynaptic density
    evidence_type: IEA
    original_reference_id: GO_REF:0000107
    review:
      summary: This annotation is transferred from mouse ortholog. Postsynaptic
        density localization is not a well-characterized feature of EIF3E
        function.
      action: KEEP_AS_NON_CORE
      reason: While eIF3 components may be present at synapses for local protein
        synthesis, this is not a core localization or function of EIF3E. The
        annotation is based on ortholog transfer rather than direct experimental
        evidence for human EIF3E.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:10504338
    review:
      summary: This publication demonstrates interaction between EIF3E (Int-6)
        and TRIM27 (Ret finger protein), as well as EIF3C. These interactions
        were identified by yeast two-hybrid and confirmed by
        co-immunoprecipitation.
      action: KEEP_AS_NON_CORE
      reason: While the protein-protein interaction is valid, "protein binding"
        is too vague. The interaction with TRIM27 and eIF3C subunits is
        biologically meaningful but the general term is uninformative.
      supported_by:
        - reference_id: PMID:10504338
          supporting_text: Interaction between the Ret finger protein and the
            Int-6 gene product and co-localisation into nuclear bodies.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:16189514
    review:
      summary: Large-scale protein-protein interaction mapping study. The
        specific interaction partners are not detailed in this annotation.
      action: KEEP_AS_NON_CORE
      reason: High-throughput interaction data. The general "protein binding"
        annotation is uninformative but the data may be useful for network
        analyses.
      supported_by:
        - reference_id: PMID:16189514
          supporting_text: Towards a proteome-scale map of the human
            protein-protein interaction network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17324924
    review:
      summary: This study demonstrates EIF3E interaction with EPAS1 (HIF-2alpha)
        and its role in targeting EPAS1 for proteasomal degradation.
      action: KEEP_AS_NON_CORE
      reason: The interaction with EPAS1 is interesting but represents a
        specialized function in hypoxia response regulation, not a core function
        of EIF3E in translation.
      supported_by:
        - reference_id: PMID:17324924
          supporting_text: 2007 Feb 26. Mammalian tumor suppressor Int6
            specifically targets hypoxia inducible factor 2 alpha for
            degradation by hypoxia- and pVHL-independent regulation.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17353931
    review:
      summary: Large-scale mass spectrometry-based protein-protein interaction
        mapping. Identified interaction with EIF3A.
      action: KEEP_AS_NON_CORE
      reason: High-throughput data. EIF3E interaction with other eIF3 subunits
        is expected as part of complex assembly.
      supported_by:
        - reference_id: PMID:17353931
          supporting_text: Large-scale mapping of human protein-protein
            interactions by mass spectrometry.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18599441
    review:
      summary: Comprehensive mass spectrometry study revealing the complete eIF3
        subunit interaction map. Demonstrates EIF3E interactions with EIF3B,
        EIF3C, EIF3D, EIF3K, EIF3L, and EIF3A.
      action: ACCEPT
      reason: This key study maps the complete eIF3 subunit interactions. EIF3E
        interactions with other eIF3 subunits are essential for complex assembly
        and function. While "protein binding" is general, these are functionally
        important interactions.
      supported_by:
        - reference_id: PMID:18599441
          supporting_text: Mass spectrometry reveals modularity and a complete
            subunit interaction map of the eukaryotic translation factor eIF3
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:18628297
    review:
      summary: Study showing DDX3 (DEAD-box RNA helicase) interaction with eIF3
        including EIF3B.
      action: KEEP_AS_NON_CORE
      reason: DDX3 interaction with eIF3 is interesting for understanding
        translation regulation but is not a core function of EIF3E specifically.
      supported_by:
        - reference_id: PMID:18628297
          supporting_text: Jul 15. Human DDX3 functions in translation and
            interacts with the translation initiation factor eIF3.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:19748344
    review:
      summary: Gas-phase mass spectrometry study of multiprotein assemblies.
        Confirms EIF3E interactions with EIF3K and EIF3L subunits.
      action: ACCEPT
      reason: Confirms eIF3 subunit interactions. EIF3E, EIF3K, and EIF3L are
        part of the same module within eIF3.
      supported_by:
        - reference_id: PMID:19748344
          supporting_text: Subunit architecture of multiprotein assemblies
            determined using restraints from gas-phase measurements
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:20890303
    review:
      summary: Study showing Int6/EIF3E regulates both proteasomal degradation
        and translation initiation in mammary epithelium. Confirms interaction
        with EIF3D.
      action: ACCEPT
      reason: EIF3E-EIF3D interaction is functionally important as they form the
        d-e module within eIF3 that promotes selective translation of
        membrane/mitochondrial proteins.
      supported_by:
        - reference_id: PMID:20890303
          supporting_text: Int6 regulates both proteasomal degradation and
            translation initiation and is critical for proper formation of acini
            by human mammary epithelium
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21988832
    review:
      summary: Human liver protein interaction network study. Identifies EIF3E
        interaction with NPM1.
      action: KEEP_AS_NON_CORE
      reason: High-throughput interactome data. NPM1 interaction is not well
        characterized functionally for EIF3E.
      supported_by:
        - reference_id: PMID:21988832
          supporting_text: Toward an understanding of the protein interaction
            network of the human liver.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:22190034
    review:
      summary: HIV-human protein interaction study. Identifies interaction with
        viral proteins.
      action: KEEP_AS_NON_CORE
      reason: Viral protein interactions may be relevant for viral translation
        but are not core functions of EIF3E.
      supported_by:
        - reference_id: PMID:22190034
          supporting_text: Global landscape of HIV-human protein complexes.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:23623729
    review:
      summary: Architecture of human translation initiation factor 3 determined
        by cross-linking mass spectrometry. Confirms interactions between EIF3E
        and EIF3D, EIF3C, EIF3K, EIF3L.
      action: ACCEPT
      reason: Key structural study confirming EIF3E interactions within the eIF3
        complex. The cross-linking data provides spatial information about
        subunit organization.
      supported_by:
        - reference_id: PMID:23623729
          supporting_text: Architecture of human translation initiation factor 3
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:24705354
    review:
      summary: Study of HIP14 (ZDHHC17) interactors relevant to Huntington's
        disease. EIF3E identified as an interactor.
      action: KEEP_AS_NON_CORE
      reason: The interaction with HIP14 is not well characterized for EIF3E
        function. May be relevant for understanding palmitoylation of
        translation factors.
      supported_by:
        - reference_id: PMID:24705354
          supporting_text: "Apr 4. The palmitoyl acyltransferase HIP14 shares a high
            proportion of interactors with huntingtin: implications for a role in
            the pathogenesis of Huntington's disease."
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:25416956
    review:
      summary: Proteome-scale human interactome network. High-throughput
        interaction data.
      action: KEEP_AS_NON_CORE
      reason: High-throughput interactome data. General protein binding
        annotation is uninformative.
      supported_by:
        - reference_id: PMID:25416956
          supporting_text: A proteome-scale map of the human interactome
            network.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:26496610
    review:
      summary: Human interactome organized by stoichiometries and abundances.
        Confirms EIF3E-NPM1 interaction.
      action: KEEP_AS_NON_CORE
      reason: High-throughput interactome data. NPM1 interaction is not a core
        function.
      supported_by:
        - reference_id: PMID:26496610
          supporting_text: Oct 22. A human interactome in three quantitative
            dimensions organized by stoichiometries and abundances.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:28514442
    review:
      summary: Architecture of human interactome study. Confirms interactions
        with multiple eIF3 subunits.
      action: ACCEPT
      reason: Confirms eIF3 subunit interactions essential for complex assembly.
      supported_by:
        - reference_id: PMID:28514442
          supporting_text: Architecture of the human interactome defines protein
            communities and disease networks
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:30833792
    review:
      summary: Protein interaction network of interferon-stimulated genes. EIF3E
        interacts with CD74 and DDX60.
      action: KEEP_AS_NON_CORE
      reason: Interactions relevant to interferon response but not core EIF3E
        function.
      supported_by:
        - reference_id: PMID:30833792
          supporting_text: Mar 4. A protein-interaction network of
            interferon-stimulated genes extends the innate immune system
            landscape.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:31515488
    review:
      summary: Study of genetic variant effects on protein interactions.
      action: KEEP_AS_NON_CORE
      reason: High-throughput variant effect data. General protein binding is
        uninformative.
      supported_by:
        - reference_id: PMID:31515488
          supporting_text: Extensive disruption of protein interactions by
            genetic variants across the allele frequency spectrum in human
            populations.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32296183
    review:
      summary: Reference binary protein interactome map. Multiple interaction
        partners identified.
      action: KEEP_AS_NON_CORE
      reason: High-throughput interactome data. General protein binding is
        uninformative.
      supported_by:
        - reference_id: PMID:32296183
          supporting_text: Apr 8. A reference map of the human binary protein
            interactome.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:32814053
    review:
      summary: Interactome mapping of neurodegenerative disease proteins.
        Multiple interactions identified including with CRYAA, PRKCA, YWHAG.
      action: KEEP_AS_NON_CORE
      reason: Potentially relevant to EIF3E role in neurodegeneration but not
        core translation function.
      supported_by:
        - reference_id: PMID:32814053
          supporting_text: Interactome Mapping Provides a Network of
            Neurodegenerative Disease Proteins and Uncovers Widespread Protein
            Aggregation in Affected Brains.
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:33961781
    review:
      summary: Cell-specific interactome remodeling study. Confirms eIF3 subunit
        interactions.
      action: ACCEPT
      reason: Confirms core eIF3 complex interactions.
      supported_by:
        - reference_id: PMID:33961781
          supporting_text: Dual proteome-scale networks reveal cell-specific
            remodeling of the human interactome
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:35271311
    review:
      summary: OpenCell endogenous tagging study. Confirms EIF3E interactions
        with EIF3B, EIF3A, EIF3K.
      action: ACCEPT
      reason: Endogenous protein localization and interaction study. Confirms
        core eIF3 subunit interactions and cytoplasmic localization.
      supported_by:
        - reference_id: PMID:35271311
          supporting_text: 'OpenCell: Endogenous tagging for the cartography of human
            cellular organization'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:39251607
    review:
      summary: Post-transcriptional regulatory module study. EIF3E interaction
        with NPM1.
      action: KEEP_AS_NON_CORE
      reason: High-throughput data. NPM1 interaction is not a core EIF3E
        function.
      supported_by:
        - reference_id: PMID:39251607
          supporting_text: Systematic identification of post-transcriptional
            regulatory modules.
  - term:
      id: GO:0001732
      label: formation of cytoplasmic translation initiation complex
    evidence_type: NAS
    original_reference_id: PMID:16920360
    review:
      summary: Review article describing eIF3 as a versatile scaffold for
        translation initiation complexes. EIF3E participates in formation of
        these complexes as an eIF3 subunit.
      action: ACCEPT
      reason: Core function. eIF3 is essential for translation initiation
        complex formation and EIF3E is an integral component.
      supported_by:
        - reference_id: PMID:16920360
          supporting_text: 'eIF3: a versatile scaffold for translation initiation
            complexes'
  - term:
      id: GO:0005852
      label: eukaryotic translation initiation factor 3 complex
    evidence_type: IPI
    original_reference_id: PMID:17322308
    review:
      summary: Mass spectrometry characterization of the human eIF3 complex
        identifying all 13 subunits including EIF3E.
      action: ACCEPT
      reason: Definitive experimental evidence for EIF3E as a component of the
        eIF3 complex.
      supported_by:
        - reference_id: PMID:17322308
          supporting_text: Structural characterization of the human eukaryotic
            initiation factor 3 protein complex by mass spectrometry
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: IDA
    original_reference_id: GO_REF:0000052
    review:
      summary: Immunofluorescence data showing cytosolic localization. EIF3E is
        predominantly cytoplasmic where it functions in translation initiation.
      action: ACCEPT
      reason: Core localization. Cytosolic localization is well established for
        EIF3E as part of the translation machinery.
      supported_by:
        - reference_id: PMID:35271311
          supporting_text: 'OpenCell: Endogenous tagging for the cartography of human
            cellular organization'
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:21745818
    review:
      summary: Study of BZW2/5MP1, an eIF5-mimic protein that interacts with
        eIF3 including EIF3E.
      action: ACCEPT
      reason: BZW2 interaction with eIF3 is functionally relevant for
        translational regulation.
      supported_by:
        - reference_id: PMID:21745818
          supporting_text: Mechanisms of translational regulation by a human
            eIF5-mimic protein
  - term:
      id: GO:0006446
      label: regulation of translational initiation
    evidence_type: ISS
    original_reference_id: GO_REF:0000024
    review:
      summary: EIF3E regulates translational initiation as part of the eIF3
        complex. The complex can both activate and repress translation of
        specific mRNAs.
      action: ACCEPT
      reason: Core function. eIF3 regulates translation initiation both
        positively and negatively for different mRNA targets.
      supported_by:
        - reference_id: PMID:25849773
          supporting_text: eIF3 targets cell-proliferation messenger RNAs for
            translational activation or repression
  - term:
      id: GO:0045296
      label: cadherin binding
    evidence_type: HDA
    original_reference_id: PMID:25468996
    review:
      summary: E-cadherin interactome study. EIF3E identified as an interactor
        of E-cadherin complex.
      action: KEEP_AS_NON_CORE
      reason: Cadherin binding is not a core function of EIF3E. This may reflect
        association with membrane-localized translation machinery near adhesion
        junctions.
      supported_by:
        - reference_id: PMID:25468996
          supporting_text: E-cadherin interactome complexity and robustness
            resolved by quantitative proteomics.
  - term:
      id: GO:0045727
      label: positive regulation of translation
    evidence_type: IPI
    original_reference_id: PMID:24092755
    review:
      summary: Study showing eIF4G binds to eIF3c, eIF3d, and eIF3e to promote
        mRNA recruitment to the ribosome, thereby positively regulating
        translation.
      action: ACCEPT
      reason: Core function. EIF3E participates in positive regulation of
        translation through interaction with eIF4G which bridges the cap-binding
        complex to the ribosome.
      supported_by:
        - reference_id: PMID:24092755
          supporting_text: Human eukaryotic initiation factor 4G (eIF4G) protein
            binds to eIF3c, -d, and -e to promote mRNA recruitment to the
            ribosome
  - term:
      id: GO:0003743
      label: translation initiation factor activity
    evidence_type: IDA
    original_reference_id: PMID:25849773
    review:
      summary: Direct demonstration that eIF3 targets cell-proliferation mRNAs
        for translational activation or repression. EIF3E contributes to this
        activity.
      action: ACCEPT
      reason: Core molecular function. This study provides direct evidence for
        eIF3 translation initiation factor activity and mRNA-selective
        regulation.
      supported_by:
        - reference_id: PMID:25849773
          supporting_text: eIF3 targets cell-proliferation messenger RNAs for
            translational activation or repression
  - term:
      id: GO:0005852
      label: eukaryotic translation initiation factor 3 complex
    evidence_type: IDA
    original_reference_id: PMID:25849773
    review:
      summary: Study directly demonstrating eIF3 complex function in
        mRNA-selective translation.
      action: ACCEPT
      reason: Core annotation. Direct experimental evidence for EIF3E as a
        component of functional eIF3 complex.
      supported_by:
        - reference_id: PMID:25849773
          supporting_text: eIF3 targets cell-proliferation messenger RNAs for
            translational activation or repression
  - term:
      id: GO:0016020
      label: membrane
    evidence_type: HDA
    original_reference_id: PMID:19946888
    review:
      summary: NK cell membrane proteome study identifying EIF3E. This may
        reflect association with membrane-localized polysomes.
      action: KEEP_AS_NON_CORE
      reason: Membrane association is not a core feature of EIF3E. May reflect
        localized translation at endoplasmic reticulum or plasma membrane.
      supported_by:
        - reference_id: PMID:19946888
          supporting_text: Defining the membrane proteome of NK cells.
  - term:
      id: GO:0003723
      label: RNA binding
    evidence_type: HDA
    original_reference_id: PMID:22681889
    review:
      summary: mRNA-bound proteome study identifying EIF3E. As a translation
        factor, EIF3E is expected to associate with mRNA.
      action: ACCEPT
      reason: RNA binding is a core function of eIF3. The complex directly binds
        to specific mRNA structures to regulate translation.
      supported_by:
        - reference_id: PMID:22681889
          supporting_text: The mRNA-bound proteome and its global occupancy
            profile on protein-coding transcripts
        - reference_id: PMID:25849773
          supporting_text: eIF3 targets cell-proliferation messenger RNAs for
            translational activation or repression
  - term:
      id: GO:0070062
      label: extracellular exosome
    evidence_type: HDA
    original_reference_id: PMID:20458337
    review:
      summary: B-cell exosome proteome study. EIF3E identified in exosomes.
      action: KEEP_AS_NON_CORE
      reason: Exosomal localization is not a core function. Many cytoplasmic
        proteins are found in exosomes.
      supported_by:
        - reference_id: PMID:20458337
          supporting_text: 2010 May 11. MHC class II-associated proteins in
            B-cell exosomes and potential functional implications for exosome
            biogenesis.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-156808
    review:
      summary: Reactome annotation for translation initiation complex formation.
        EIF3E is cytosolic where it functions in translation.
      action: ACCEPT
      reason: Cytosolic localization is core for translation function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-156823
    review:
      summary: Reactome annotation. Redundant cytosol annotation.
      action: ACCEPT
      reason: Core localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-157849
    review:
      summary: Reactome annotation. Redundant cytosol annotation.
      action: ACCEPT
      reason: Core localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-72619
    review:
      summary: Reactome annotation for eIF2:GTP hydrolysis and eIF release.
      action: ACCEPT
      reason: Core localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-72621
    review:
      summary: Reactome annotation for ribosomal scanning.
      action: ACCEPT
      reason: Core localization.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-72676
    review:
      summary: Reactome annotation for eIF3 and eIF1A binding to 40S subunit.
      action: ACCEPT
      reason: Core localization and function.
      supported_by:
        - reference_id: Reactome:R-HSA-72676
          supporting_text: eIF3 and eIF1A bind to the 40S subunit
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-72691
    review:
      summary: Reactome annotation for 43S pre-initiation complex formation.
      action: ACCEPT
      reason: Core localization and function.
  - term:
      id: GO:0005829
      label: cytosol
    evidence_type: TAS
    original_reference_id: Reactome:R-HSA-72697
    review:
      summary: Reactome annotation for start codon recognition.
      action: ACCEPT
      reason: Core localization and function.
  - term:
      id: GO:0000184
      label: nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
    evidence_type: IMP
    original_reference_id: PMID:17468741
    review:
      summary: Key study demonstrating that EIF3E/INT6 is required for
        nonsense-mediated mRNA decay. EIF3E knockdown specifically inhibits NMD
        without affecting general translation, establishing it as a specialized
        NMD factor.
      action: ACCEPT
      reason: Core specialized function. EIF3E is uniquely required for NMD
        through its role in pioneer round translation and interaction with UPF2
        and CBP80.
      supported_by:
        - reference_id: PMID:17468741
          supporting_text: Human INT6/eIF3e is required for nonsense-mediated
            mRNA decay
  - term:
      id: GO:0000785
      label: chromatin
    evidence_type: NAS
    original_reference_id: PMID:17468741
    review:
      summary: This annotation suggests chromatin localization based on the NMD
        study. However, the primary evidence in this paper relates to NMD
        function rather than direct chromatin association.
      action: UNDECIDED
      reason: The evidence for chromatin localization is not clear from the
        cited reference. The paper primarily addresses NMD function and nuclear
        localization but not direct chromatin association.
      supported_by:
        - reference_id: PMID:17468741
          supporting_text: Human INT6/eIF3e is required for nonsense-mediated
            mRNA decay.
  - term:
      id: GO:0003743
      label: translation initiation factor activity
    evidence_type: IC
    original_reference_id: PMID:17322308
    review:
      summary: Inferred from EIF3E membership in the eIF3 complex demonstrated
        by mass spectrometry.
      action: ACCEPT
      reason: Core molecular function. Translation initiation factor activity is
        correctly inferred from complex membership.
      supported_by:
        - reference_id: PMID:17322308
          supporting_text: Structural characterization of the human eukaryotic
            initiation factor 3 protein complex by mass spectrometry
  - term:
      id: GO:0003743
      label: translation initiation factor activity
    evidence_type: IDA
    original_reference_id: PMID:17581632
    review:
      summary: Biochemical reconstitution study demonstrating that a six-subunit
        complex including EIF3E has translation initiation activity.
      action: ACCEPT
      reason: Core molecular function. Direct experimental evidence from
        reconstituted complex.
      supported_by:
        - reference_id: PMID:17581632
          supporting_text: Reconstitution reveals the functional core of
            mammalian eIF3
  - term:
      id: GO:0003743
      label: translation initiation factor activity
    evidence_type: IC
    original_reference_id: PMID:18599441
    review:
      summary: Inferred from EIF3E as a component of the complete eIF3 complex
        mapped by mass spectrometry.
      action: ACCEPT
      reason: Core molecular function.
      supported_by:
        - reference_id: PMID:18599441
          supporting_text: Mass spectrometry reveals modularity and a complete
            subunit interaction map of the eukaryotic translation factor eIF3
  - term:
      id: GO:0005515
      label: protein binding
    evidence_type: IPI
    original_reference_id: PMID:17468741
    review:
      summary: NMD study demonstrating EIF3E interaction with UPF2, EIF4G1,
        NCBP1 (CBP80), and other eIF3 subunits.
      action: ACCEPT
      reason: Important interactions for NMD function. EIF3E-UPF2 and
        EIF3E-CBP80 interactions are essential for pioneer round translation and
        NMD.
      supported_by:
        - reference_id: PMID:17468741
          supporting_text: Human INT6/eIF3e is required for nonsense-mediated
            mRNA decay
  - term:
      id: GO:0005634
      label: nucleus
    evidence_type: IDA
    original_reference_id: PMID:10504338
    review:
      summary: Immunofluorescence demonstrating nuclear localization of EIF3E,
        including co-localization with PML bodies.
      action: ACCEPT
      reason: Direct experimental evidence for nuclear localization. The nuclear
        pool of EIF3E is functionally important for pioneer round translation
        and NMD.
      supported_by:
        - reference_id: PMID:10504338
          supporting_text: Interaction between the Ret finger protein and the
            Int-6 gene product and co-localisation into nuclear bodies
  - term:
      id: GO:0005852
      label: eukaryotic translation initiation factor 3 complex
    evidence_type: NAS
    original_reference_id: PMID:10504338
    review:
      summary: Study identifying EIF3E interactions including with EIF3C,
        supporting eIF3 complex membership.
      action: ACCEPT
      reason: Core annotation. eIF3 complex membership is well established.
      supported_by:
        - reference_id: PMID:10504338
          supporting_text: Interaction between the Ret finger protein and the
            Int-6 gene product and co-localisation into nuclear bodies
  - term:
      id: GO:0005852
      label: eukaryotic translation initiation factor 3 complex
    evidence_type: IDA
    original_reference_id: PMID:17322308
    review:
      summary: Mass spectrometry identification of EIF3E as a component of the
        purified eIF3 complex.
      action: ACCEPT
      reason: Definitive experimental evidence for eIF3 complex membership.
      supported_by:
        - reference_id: PMID:17322308
          supporting_text: Structural characterization of the human eukaryotic
            initiation factor 3 protein complex by mass spectrometry
  - term:
      id: GO:0005852
      label: eukaryotic translation initiation factor 3 complex
    evidence_type: IDA
    original_reference_id: PMID:17581632
    review:
      summary: Reconstitution study showing EIF3E is part of the functional eIF3
        complex.
      action: ACCEPT
      reason: Core annotation. Direct biochemical evidence.
      supported_by:
        - reference_id: PMID:17581632
          supporting_text: Reconstitution reveals the functional core of
            mammalian eIF3
  - term:
      id: GO:0005852
      label: eukaryotic translation initiation factor 3 complex
    evidence_type: IDA
    original_reference_id: PMID:18599441
    review:
      summary: Complete subunit interaction map of eIF3 by mass spectrometry
        confirming EIF3E as a subunit.
      action: ACCEPT
      reason: Core annotation. Comprehensive structural characterization.
      supported_by:
        - reference_id: PMID:18599441
          supporting_text: Mass spectrometry reveals modularity and a complete
            subunit interaction map of the eukaryotic translation factor eIF3
  - term:
      id: GO:0006413
      label: translational initiation
    evidence_type: IC
    original_reference_id: PMID:17322308
    review:
      summary: Inferred from eIF3 complex membership.
      action: ACCEPT
      reason: Core biological process.
      supported_by:
        - reference_id: PMID:17322308
          supporting_text: Structural characterization of the human eukaryotic
            initiation factor 3 protein complex by mass spectrometry
  - term:
      id: GO:0006413
      label: translational initiation
    evidence_type: IDA
    original_reference_id: PMID:17581632
    review:
      summary: Direct demonstration of translational initiation activity for
        reconstituted eIF3 containing EIF3E.
      action: ACCEPT
      reason: Core biological process. Direct biochemical evidence.
      supported_by:
        - reference_id: PMID:17581632
          supporting_text: Reconstitution reveals the functional core of
            mammalian eIF3
  - term:
      id: GO:0006413
      label: translational initiation
    evidence_type: IC
    original_reference_id: PMID:18599441
    review:
      summary: Inferred from eIF3 complex membership.
      action: ACCEPT
      reason: Core biological process.
      supported_by:
        - reference_id: PMID:18599441
          supporting_text: Mass spectrometry reveals modularity and a complete
            subunit interaction map of the eukaryotic translation factor eIF3
  - term:
      id: GO:0006446
      label: regulation of translational initiation
    evidence_type: NAS
    original_reference_id: PMID:17468741
    review:
      summary: EIF3E regulates translational initiation, particularly in the
        context of NMD and pioneer round translation.
      action: ACCEPT
      reason: Core function. EIF3E regulates translation initiation both
        positively (general translation) and negatively (NMD substrates).
      supported_by:
        - reference_id: PMID:17468741
          supporting_text: Human INT6/eIF3e is required for nonsense-mediated
            mRNA decay
  - term:
      id: GO:0016605
      label: PML body
    evidence_type: IDA
    original_reference_id: PMID:10504338
    review:
      summary: Immunofluorescence demonstrating EIF3E co-localization with PML
        bodies in the nucleus.
      action: ACCEPT
      reason: Direct experimental evidence for PML body localization.
      supported_by:
        - reference_id: PMID:10504338
          supporting_text: Interaction between the Ret finger protein and the
            Int-6 gene product and co-localisation into nuclear bodies
  - term:
      id: GO:0045947
      label: negative regulation of translational initiation
    evidence_type: NAS
    original_reference_id: PMID:10504338
    review:
      summary: EIF3E can negatively regulate translation, particularly through
        its role in NMD where it diverts mRNAs from translation to degradation.
      action: ACCEPT
      reason: EIF3E participates in negative regulation of translation through
        NMD and through eIF3-mediated translational repression of specific mRNAs
        like BTG1.
      supported_by:
        - reference_id: PMID:17468741
          supporting_text: Human INT6/eIF3e is required for nonsense-mediated
            mRNA decay
        - reference_id: PMID:25849773
          supporting_text: eIF3 targets cell-proliferation messenger RNAs for
            translational activation or repression
        - reference_id: PMID:10504338
          supporting_text: Interaction between the Ret finger protein and the
            Int-6 gene product and co-localisation into nuclear bodies.
  - term:
      id: GO:0003743
      label: translation initiation factor activity
    evidence_type: IC
    original_reference_id: PMID:9295280
    review:
      summary: Original identification of EIF3E (INT-6) as the p48 subunit of
        eIF3, establishing its role as a translation initiation factor.
      action: ACCEPT
      reason: Foundational study establishing EIF3E as a translation initiation
        factor.
      supported_by:
        - reference_id: PMID:9295280
          supporting_text: The translation initiation factor eIF3-p48 subunit is
            encoded by int-6, a site of frequent integration by the mouse
            mammary tumor virus genome
  - term:
      id: GO:0005654
      label: nucleoplasm
    evidence_type: NAS
    original_reference_id: PMID:17468741
    review:
      summary: Nuclear localization of EIF3E includes nucleoplasm, where it
        participates in pioneer round translation and NMD.
      action: ACCEPT
      reason: EIF3E nuclear localization is well established and functionally
        important.
      supported_by:
        - reference_id: PMID:17468741
          supporting_text: Human INT6/eIF3e is required for nonsense-mediated
            mRNA decay
  - term:
      id: GO:0005737
      label: cytoplasm
    evidence_type: IDA
    original_reference_id: PMID:10504338
    review:
      summary: Immunofluorescence showing cytoplasmic localization of EIF3E.
      action: ACCEPT
      reason: Core localization. Cytoplasm is the primary site of translation
        initiation.
      supported_by:
        - reference_id: PMID:10504338
          supporting_text: Interaction between the Ret finger protein and the
            Int-6 gene product and co-localisation into nuclear bodies
  - term:
      id: GO:0005852
      label: eukaryotic translation initiation factor 3 complex
    evidence_type: IDA
    original_reference_id: PMID:9295280
    review:
      summary: Original identification of EIF3E as the p48 subunit of the
        purified eIF3 complex.
      action: ACCEPT
      reason: Foundational study establishing EIF3E as an eIF3 subunit.
      supported_by:
        - reference_id: PMID:9295280
          supporting_text: The translation initiation factor eIF3-p48 subunit is
            encoded by int-6, a site of frequent integration by the mouse
            mammary tumor virus genome
  - term:
      id: GO:0006446
      label: regulation of translational initiation
    evidence_type: NAS
    original_reference_id: PMID:9295280
    review:
      summary: Original study describing EIF3E as a translation initiation
        factor involved in regulating initiation.
      action: ACCEPT
      reason: Core function established in foundational study.
      supported_by:
        - reference_id: PMID:9295280
          supporting_text: The translation initiation factor eIF3-p48 subunit is
            encoded by int-6, a site of frequent integration by the mouse
            mammary tumor virus genome
references:
  - id: GO_REF:0000024
    title: Manual transfer of experimentally-verified manual GO annotation data
      to orthologs by curator judgment of sequence similarity.
    findings: []
  - id: GO_REF:0000033
    title: Annotation inferences using phylogenetic trees
    findings:
      - statement: EIF3E is a conserved eIF3 subunit with orthologs across
          eukaryotes supporting translational initiation function
  - id: GO_REF:0000043
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword
      mapping
    findings: []
  - id: GO_REF:0000044
    title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular
      Location vocabulary mapping
    findings: []
  - id: GO_REF:0000052
    title: Gene Ontology annotation based on curation of immunofluorescence data
    findings: []
  - id: GO_REF:0000104
    title: Electronic Gene Ontology annotations created by transferring manual
      GO annotations between related proteins based on shared sequence features
    findings: []
  - id: GO_REF:0000107
    title: Automatic transfer of experimentally verified manual GO annotation
      data to orthologs using Ensembl Compara
    findings: []
  - id: GO_REF:0000117
    title: Electronic Gene Ontology annotations created by ARBA machine learning
      models
    findings: []
  - id: GO_REF:0000120
    title: Combined Automated Annotation using Multiple IEA Methods
    findings: []
  - id: PMID:9295280
    title: The translation initiation factor eIF3-p48 subunit is encoded by
      int-6, a site of frequent integration by the mouse mammary tumor virus
      genome
    findings:
      - statement: Original identification of EIF3E as the p48 subunit of human
          eIF3
      - statement: Interaction with EIF3A demonstrated
      - statement: Ubiquitous tissue expression
  - id: PMID:10504338
    title: Interaction between the Ret finger protein and the Int-6 gene product
      and co-localisation into nuclear bodies
    findings:
      - statement: EIF3E interacts with TRIM27 (Ret finger protein) and EIF3C
      - statement: Nuclear and cytoplasmic localization demonstrated by
          immunofluorescence
      - statement: Co-localization with PML bodies in nucleus
  - id: PMID:16920360
    title: 'eIF3: a versatile scaffold for translation initiation complexes'
    findings:
      - statement: Review describing eIF3 structure and function
      - statement: eIF3 serves as scaffold for translation initiation complex
          assembly
  - id: PMID:17322308
    title: Structural characterization of the human eukaryotic initiation factor
      3 protein complex by mass spectrometry
    findings:
      - statement: Mass spectrometry identification of all 13 eIF3 subunits
      - statement: EIF3E confirmed as integral component
      - statement: N-terminal acetylation of EIF3E
  - id: PMID:17468741
    title: Human INT6/eIF3e is required for nonsense-mediated mRNA decay
    findings:
      - statement: EIF3E is specifically required for NMD
      - statement: EIF3E interacts with CBP80 and UPF2
      - statement: EIF3E functions in pioneer round translation
      - statement: EIF3E knockdown inhibits NMD without affecting general
          translation
  - id: PMID:17581632
    title: Reconstitution reveals the functional core of mammalian eIF3
    findings:
      - statement: Six-subunit complex including EIF3E has translation
          initiation activity
      - statement: EIF3E is essential for eIF3 complex assembly and function
  - id: PMID:18599441
    title: Mass spectrometry reveals modularity and a complete subunit
      interaction map of the eukaryotic translation factor eIF3
    findings:
      - statement: Complete eIF3 subunit interaction map
      - statement: EIF3E is part of module C with EIF3C, EIF3D, EIF3K, EIF3L
      - statement: EIF3E interacts directly with EIF3B, EIF3D, EIF3K, EIF3L
  - id: PMID:23623729
    title: Architecture of human translation initiation factor 3
    findings:
      - statement: Cross-linking mass spectrometry of eIF3 architecture
      - statement: Spatial organization of EIF3E within the complex
  - id: PMID:24092755
    title: Human eukaryotic initiation factor 4G (eIF4G) protein binds to eIF3c,
      -d, and -e to promote mRNA recruitment to the ribosome
    findings:
      - statement: EIF3E interacts with eIF4G
      - statement: This interaction promotes mRNA recruitment to ribosomes
  - id: PMID:25849773
    title: eIF3 targets cell-proliferation messenger RNAs for translational
      activation or repression
    findings:
      - statement: eIF3 selectively regulates translation of specific mRNAs
      - statement: eIF3 can both activate and repress translation of target
          mRNAs
      - statement: c-Jun mRNA translation is activated by eIF3
      - statement: BTG1 mRNA translation is repressed by eIF3
  - id: PMID:16189514
    title: Towards a proteome-scale map of the human protein-protein interaction
      network
    findings: []
  - id: PMID:17324924
    title: Mammalian tumor suppressor Int6 specifically targets hypoxia
      inducible factor 2 alpha for degradation by hypoxia- and pVHL-independent
      regulation
    findings: []
  - id: PMID:17353931
    title: Large-scale mapping of human protein-protein interactions by mass
      spectrometry
    findings: []
  - id: PMID:18628297
    title: Human DDX3 functions in translation and interacts with the
      translation initiation factor eIF3
    findings: []
  - id: PMID:19748344
    title: Subunit architecture of multiprotein assemblies determined using
      restraints from gas-phase measurements
    findings: []
  - id: PMID:20890303
    title: Int6 regulates both proteasomal degradation and translation
      initiation and is critical for proper formation of acini by human mammary
      epithelium
    findings: []
  - id: PMID:21988832
    title: Toward an understanding of the protein interaction network of the
      human liver
    findings: []
  - id: PMID:22190034
    title: Global landscape of HIV-human protein complexes
    findings: []
  - id: PMID:24705354
    title: 'The palmitoyl acyltransferase HIP14 shares a high proportion of interactors with huntingtin: implications for a role in the pathogenesis of Huntington''s disease.'
    findings: []
  - id: PMID:25416956
    title: A proteome-scale map of the human interactome network
    findings: []
  - id: PMID:26496610
    title: A human interactome in three quantitative dimensions organized by
      stoichiometries and abundances
    findings: []
  - id: PMID:28514442
    title: Architecture of the human interactome defines protein communities and
      disease networks
    findings: []
  - id: PMID:30833792
    title: A protein-interaction network of interferon-stimulated genes extends
      the innate immune system landscape
    findings: []
  - id: PMID:31515488
    title: Extensive disruption of protein interactions by genetic variants
      across the allele frequency spectrum in human populations
    findings: []
  - id: PMID:32296183
    title: A reference map of the human binary protein interactome
    findings: []
  - id: PMID:32814053
    title: Interactome Mapping Provides a Network of Neurodegenerative Disease
      Proteins and Uncovers Widespread Protein Aggregation in Affected Brains
    findings: []
  - id: PMID:33961781
    title: Dual proteome-scale networks reveal cell-specific remodeling of the
      human interactome
    findings: []
  - id: PMID:35271311
    title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization'
    findings: []
  - id: PMID:39251607
    title: Systematic identification of post-transcriptional regulatory modules
    findings: []
  - id: PMID:21745818
    title: Mechanisms of translational regulation by a human eIF5-mimic protein
    findings: []
  - id: PMID:25468996
    title: E-cadherin interactome complexity and robustness resolved by
      quantitative proteomics
    findings: []
  - id: PMID:19946888
    title: Defining the membrane proteome of NK cells
    findings: []
  - id: PMID:22681889
    title: The mRNA-bound proteome and its global occupancy profile on
      protein-coding transcripts
    findings: []
  - id: PMID:20458337
    title: MHC class II-associated proteins in B-cell exosomes and potential
      functional implications for exosome biogenesis
    findings: []
  - id: Reactome:R-HSA-156808
    title: Formation of translation initiation complexes yielding circularized
      Ceruloplasmin mRNA in a closed-loop conformation
    findings: []
  - id: Reactome:R-HSA-156823
    title: Association of phospho-L13a with GAIT element of Ceruloplasmin mRNA
    findings: []
  - id: Reactome:R-HSA-157849
    title: Formation of translation initiation complexes containing mRNA that
      does not circularize
    findings: []
  - id: Reactome:R-HSA-72619
    title: eIF2-GTP is hydrolyzed, eIFs are released
    findings: []
  - id: Reactome:R-HSA-72621
    title: Ribosomal scanning
    findings: []
  - id: Reactome:R-HSA-72676
    title: eIF3 and eIF1A bind to the 40S subunit
    findings: []
  - id: Reactome:R-HSA-72691
    title: Formation of the 43S pre-initiation complex
    findings: []
  - id: Reactome:R-HSA-72697
    title: Start codon recognition
    findings: []
  - id: file:human/EIF3E/EIF3E-deep-research-perplexity.md
    title: Deep research on EIF3E function
    findings: []
core_functions:
  - description: EIF3E is an integral component of the 13-subunit human eIF3
      complex, forming part of module C with EIF3C, EIF3D, EIF3K, and EIF3L. It
      contributes to translation initiation factor activity as part of the eIF3
      complex, which is required for 43S and 48S preinitiation complex formation
      and mRNA recruitment to the ribosome.
    molecular_function:
      id: GO:0003743
      label: translation initiation factor activity
    in_complex:
      id: GO:0005852
      label: eukaryotic translation initiation factor 3 complex
    locations:
      - id: GO:0005829
        label: cytosol
    directly_involved_in:
      - id: GO:0006413
        label: translational initiation
  - description: EIF3E participates in mRNA-selective translation regulation.
      The eIF3 complex can both activate (e.g., c-Jun) and repress (e.g., BTG1)
      translation of specific mRNAs through binding to 5' UTR stem-loop
      structures.
    molecular_function:
      id: GO:0003743
      label: translation initiation factor activity
    directly_involved_in:
      - id: GO:0006446
        label: regulation of translational initiation
      - id: GO:0045727
        label: positive regulation of translation
  - description: EIF3E is uniquely required for nonsense-mediated mRNA decay
      (NMD). It interacts with CBP80 and UPF2 to function in pioneer round
      translation, specifically targeting NMD substrates without affecting
      general translation.
    molecular_function:
      id: GO:0003743
      label: translation initiation factor activity
    locations:
      - id: GO:0005634
        label: nucleus
      - id: GO:0016605
        label: PML body
    directly_involved_in:
      - id: GO:0000184
        label: nuclear-transcribed mRNA catabolic process, nonsense-mediated
          decay
proposed_new_terms: []
suggested_questions:
  - question: What determines whether eIF3 binding to a specific mRNA results in
      translational activation versus repression, given that eIF3 can both
      activate (e.g., c-Jun) and repress (e.g., BTG1) translation of different
      mRNA targets through binding to 5' UTR stem-loop structures?
  - question: What is the mechanism by which EIF3E is selectively required for
      NMD but not for general translation, given that EIF3E knockdown
      specifically inhibits NMD without affecting bulk translation?
  - question: How does EIF3E nuclear-cytoplasmic shuttling relate to cell cycle
      regulation, given that nuclear EIF3E levels decrease during early S phase?
suggested_experiments:
  - description: Determine cryo-EM structures of EIF3E-containing eIF3 bound to
      specific target mRNAs to reveal how EIF3E contributes to mRNA-selective
      translation regulation.
  - description: Perform proximity labeling (BioID/APEX) of nuclear versus
      cytoplasmic EIF3E pools to identify compartment-specific interaction
      partners and functions.
  - description: Conduct ribosome profiling after acute EIF3E depletion to
      identify the specific mRNAs whose translation depends on EIF3E.

EIF3E

Gene Description

Existing Annotations Review

Core Functions

EIF3E participates in mRNA-selective translation regulation. The eIF3 complex can both activate (e.g., c-Jun) and repress (e.g., BTG1) translation of specific mRNAs through binding to 5' UTR stem-loop structures.

EIF3E is uniquely required for nonsense-mediated mRNA decay (NMD). It interacts with CBP80 and UPF2 to function in pioneer round translation, specifically targeting NMD substrates without affecting general translation.

References

Suggested Questions for Experts

Suggested Experiments

Deep Research

Falcon

Citations

Perplexity

Eukaryotic Translation Initiation Factor 3 Subunit E (EIF3E): Molecular Function, Cellular Roles, and Regulatory Biology

Molecular Architecture and Structural Organization of EIF3E

EIF3E as a Non-Core Component of the eIF3 Translation Initiation Factor

Primary Function of EIF3E within Global Translation Initiation

Specialized Roles of EIF3E in Transcript-Specific Translation Regulation

Nonsense-Mediated Decay and the Specialized Role of EIF3E in mRNA Surveillance

Cellular Localization and Subcellular Compartmentalization of EIF3E

Post-Translational Modification and Regulatory Protein Interactions of EIF3E

Functional Roles of EIF3E in Stress Responses and Cellular Adaptation

Role of EIF3E in Cancer and Dysregulation in Human Malignancies

Specialized Translation Initiation Mechanisms Involving EIF3E

Concluding Synthesis and Future Perspectives

Citations

📄 View Raw YAML