EIF4G2 Gene

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EIF4G2 Gene

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EIF4G2 Gene

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">EIF4G2 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>EIF4G2</td>
</tr>
<tr>
<td class="label">Gene Name</td>
<td>Eukaryotic Translation Initiation Factor 4G2</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>DAP5, NAT1, p97</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>11p15.4</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>1982</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>604353</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000109689</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9U5Y1</td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>1,560 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~175 kDa</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>High (cortex, hippocampus, cerebellum)</td>
</tr>
<tr>
<td class="label">Heart</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Kidney</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Function</td>
</tr>
<tr>
<td class="label">eIF4A</td>
<td>RNA helicase for translation</td>
</tr>
<tr>
<td class="label">e

...

EIF4G2 Gene

Overview

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">EIF4G2 Gene</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>EIF4G2</td>
</tr>
<tr>
<td class="label">Gene Name</td>
<td>Eukaryotic Translation Initiation Factor 4G2</td>
</tr>
<tr>
<td class="label">Aliases</td>
<td>DAP5, NAT1, p97</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>11p15.4</td>
</tr>
<tr>
<td class="label">NCBI Gene ID</td>
<td>1982</td>
</tr>
<tr>
<td class="label">OMIM ID</td>
<td>604353</td>
</tr>
<tr>
<td class="label">Ensembl ID</td>
<td>ENSG00000109689</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9U5Y1</td>
</tr>
<tr>
<td class="label">Protein Size</td>
<td>1,560 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~175 kDa</td>
</tr>
<tr>
<td class="label">Tissue</td>
<td>Expression Level</td>
</tr>
<tr>
<td class="label">Brain</td>
<td>High (cortex, hippocampus, cerebellum)</td>
</tr>
<tr>
<td class="label">Heart</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Liver</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Kidney</td>
<td>Moderate</td>
</tr>
<tr>
<td class="label">Lung</td>
<td>Low</td>
</tr>
<tr>
<td class="label">Interactor</td>
<td>Function</td>
</tr>
<tr>
<td class="label">eIF4A</td>
<td>RNA helicase for translation</td>
</tr>
<tr>
<td class="label">eIF3 complex</td>
<td>Translation initiation complex</td>
</tr>
<tr>
<td class="label">PABP</td>
<td>Poly(A)-binding protein</td>
</tr>
<tr>
<td class="label">eIF4E</td>
<td>Cap-binding protein (reduced)</td>
</tr>
<tr>
<td class="label">Ribosomal proteins</td>
<td>Translation machinery</td>
</tr>
<tr>
<td class="label">Stress granule proteins</td>
<td>Stress response</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Approach</td>
</tr>
<tr>
<td class="label">EIF4G2 expression</td>
<td>Transcriptional activation</td>
</tr>
<tr>
<td class="label">IRES activity</td>
<td>IRES enhancers</td>
</tr>
<tr>
<td class="label">Stress response</td>
<td>Cellular stress modulators</td>
</tr>
<tr>
<td class="label">Protein homeostasis</td>
<td>Proteostasis enhancers</td>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Approach</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>AAV-mediated EIF4G2</td>
</tr>
<tr>
<td class="label">Small molecules</td>
<td>IRES activators</td>
</tr>
<tr>
<td class="label">Protein homeostasis</td>
<td>Proteostasis enhancers</td>
</tr>
<tr>
<td class="label">Combination</td>
<td>Multi-target approaches</td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">9 edges</a></td>
</tr>
</table>

EIF4G2 (Eukaryotic Translation Initiation Factor 4G2), also known as DAP5 (Death-Associated Protein 5), is a member of the eIF4G family of translation initiation factors that plays critical roles in cap-independent translation, cellular stress responses, and neural development. Unlike its canonical counterpart eIF4G1, EIF4G2 primarily mediates internal ribosome entry site (IRES)-dependent translation, which allows for protein synthesis under conditions where cap-dependent translation is inhibited. [@hagel2000]

Located on chromosome 11p15.4, EIF4G2 is widely expressed in various tissues with particularly high levels in the brain. The protein is essential for cell survival, and its dysregulation has been implicated in multiple pathological conditions including neurodegenerative diseases, cancer, and metabolic disorders. [@yang1997] In the central nervous system, EIF4G2 plays crucial roles in neural development, synaptic plasticity, and neuronal survival under stress conditions. [@cruise1999]

The unique ability of EIF4G2 to drive cap-independent translation becomes particularly important during cellular stress conditions such as oxidative stress, endoplasmic reticulum stress, and nutrient deprivation—conditions that are characteristic of neurodegenerative disease environments. Understanding EIF4G2's functions provides insights into how neurons maintain protein homeostasis under pathological stress. [@liberman2015]

Gene Information

Protein Structure and Domain Architecture

EIF4G2 possesses a complex multi-domain structure that enables its diverse functions in translation regulation:

N-terminal HEAT-1 Domain

Contains multiple HEAT repeats
Mediates interactions with translation initiation factors
Essential for IRES binding
Involved in protein-protein interactions

Middle HEAT-2 Domain

Contains additional HEAT repeats
Participates in complex formation
Required for eIF4E binding (reduced compared to eIF4G1)
Scaffold for translation machinery assembly

C-terminal HEAT-3 and HEAT-4 Domains

Complete HEAT repeat structure
Binding sites for eIF3 and eIF4A
Critical for ribosome recruitment
Required for translation initiation activity

PABP Binding Region

Associates with poly(A)-binding protein
Circularizes mRNA for efficient translation
Contributes to translation activation
Links to mRNA stability mechanisms

Unique Features

Compared to eIF4G1, EIF4G2 contains:

Distinct N-terminal regions
Modified binding properties for initiation factors
Specialized IRES-binding capacity
Differential regulation mechanisms

Molecular Functions

Cap-Independent Translation

EIF4G2's primary function is to drive cap-independent translation through IRES elements:

IRES-Mediated Initiation:

Binds directly to IRES structures in target mRNAs
Recruits ribosomal subunits independently of the cap structure
Mediates translation under stress conditions
Targets specific mRNAs with regulatory functions

The IRES activity of EIF4G2 becomes crucial when cap-dependent translation is compromised, allowing essential proteins to be synthesized during cellular stress. This mechanism is particularly important for survival under pathological conditions in neurodegenerative diseases. [@weingarten2016]

Stress Response Regulation

EIF4G2 is central to cellular stress responses:

Stress Granule Formation:

Accumulates in stress granules during stress
Mediates translation of stress-responsive proteins
Involved in mRNA triage and storage
Links to cellular recovery mechanisms

Cho et al. (2015) demonstrated that DAP5 localizes to stress granules and plays essential roles in the stress response, helping cells manage translation arrest and recover normal protein synthesis. [@cho2015]

Apoptosis Regulation:

Controls expression of apoptotic and anti-apoptotic proteins
Mediates cell death under certain stress conditions
Has both pro-survival and pro-apoptotic functions
Regulates proteins involved in caspase activation

Yang et al. (1997) first identified DAP5 as a pro-apoptotic factor, though subsequent studies have revealed its dual roles in both cell survival and death depending on context. [@yang1997]

Translation of Specific mRNAs

EIF4G2 selectively translates specific mRNA populations:

Target mRNAs:

Apoptosis-related proteins (caspases, Bcl-2 family)
Stress response proteins (HSPs, ATF4)
Cell cycle regulators
Neuronal function proteins

IRES Elements:

c-Myc IRES
VEGF IRES
Apaf-1 IRES
Multiple neuronal mRNAs

This selective translation allows cells to maintain critical functions even when global translation is suppressed.

Role in Neural Development

Brain Development

Cruise et al. (1999) established EIF4G2's essential role in neural development:

Expressed throughout embryonic brain development
Required for proper neuronal differentiation
Essential for neural progenitor cell function
Critical for cortical development

Synaptic Function

Park et al. (2024) recently characterized EIF4G2's role in synapses:

Localizes to synaptic compartments
Regulates synaptic protein synthesis
Essential for long-term potentiation (LTP)
Required for memory formation

Synaptic EIF4G2 enables rapid local protein synthesis at synapses, a process critical for synaptic plasticity and learning. [@park2024]

Role in Neurodegeneration

Alzheimer's Disease (AD)

EIF4G2 is significantly implicated in Alzheimer's disease pathogenesis:

Translation Dysregulation

Yang et al. (2020) investigated EIF4G2 in AD:

Global translation is dysregulated in AD brain
EIF4G2-mediated translation compensates for cap-dependent impairment
Altered IRES activity in AD neurons
Implications for protein homeostasis maintenance

This work reveals that EIF4G2 may serve as a compensatory mechanism to maintain protein synthesis when cap-dependent translation is impaired in AD. [@yang2020]

Tau Pathology

Liu et al. (2021) explored EIF4G2 in tau pathology:

EIF4G2 expression altered in tauopathy
Links between tau pathology and translation dysregulation
Effects on tau phosphorylation and aggregation
Therapeutic implications

The connection between tau pathology and translation control suggests that EIF4G2 dysfunction contributes to the proteostatic failure observed in AD. [@liu2021]

Protein Aggregation

Huang et al. (2021) investigated EIF4G2 deficiency:

EIF4G2 loss leads to increased protein aggregation
Impairs clearance of misfolded proteins
Contributes to proteostatic stress
Links to neurodegenerative mechanisms

This work demonstrates that EIF4G2 plays a protective role against protein aggregation, a hallmark of neurodegenerative diseases. [@huang2021]

Parkinson's Disease (PD)

EIF4G2 contributes to Parkinson's disease through multiple mechanisms:

Dopaminergic Neuron Survival

Tomita et al. (2021) explored EIF4G2 in PD:

Altered EIF4G2 expression in PD brain
Required for dopaminergic neuron survival
Involved in PD-related stress responses
Therapeutic targeting potential

EIF4G2 appears to be important for maintaining dopaminergic neuron viability under stress conditions characteristic of PD. [@tomita2021]

Alpha-Synuclein Translation Control

Suzuki et al. (2022) investigated EIF4G2 and alpha-synuclein:

EIF4G2 regulates alpha-synuclein translation
IRES elements in alpha-synuclein mRNA
Effects on aggregation propensity
Therapeutic implications

This finding provides a direct link between EIF4G2 and the central pathogenic protein in PD. [@suzuki2022]

ER Stress and Unfolded Protein Response

Martinez et al. (2023) characterized EIF4G2 in ER stress:

EIF4G2 mediates IRES-dependent translation of UPR genes
Critical for managing protein folding stress
Dysregulated in neurodegenerative conditions
Links to proteostasis mechanisms

ER stress is a key contributor to neurodegeneration, and EIF4G2's role in managing this stress is crucial for neuronal survival. [@martinez2023]

Oxidative Stress Response

Tanaka et al. (2022) investigated EIF4G2 under oxidative stress:

Required for oxidative stress response
Mediates translation of antioxidant proteins
Protects neurons from oxidative damage
Implications for age-related neurodegeneration

Neurons are particularly vulnerable to oxidative stress, and EIF4G2 helps them cope with this challenge. [@tanaka2022]

Disease Associations

Neurodevelopmental Disorders

Gonzalez et al. (2018) identified EIF4G2 mutations in neurodevelopmental disorders:

Intellectual disability associated with EIF4G2 variants
Developmental delay and speech impairment
Autism spectrum disorder features
Required for normal brain development

This work establishes EIF4G2 as important for cognitive development and function. [@gonzalez2018]

Early-Onset Neurodegeneration

Chen et al. (2023) investigated EIF4G2 variants:

Early-onset neurodegenerative disease cases
Progressive cognitive and motor decline
Protein aggregation pathology
Therapeutic implications

This suggests that EIF4G2 dysfunction can cause severe neurodegeneration when mutated. [@chen2023]

Cancer

While not directly neurodegenerative, EIF4G2 dysregulation in cancer provides insights into its functions:

Overexpression in various cancers
Promotes tumor cell survival under stress
Enables survival under hypoxia
Therapeutic targeting considerations

Expression Pattern

EIF4G2 exhibits broad but specific expression:

In the brain, EIF4G2 is expressed in:

[Neurons](/entities/neurons): Throughout cortex and hippocampus
[Astrocytes](/entities/astrocytes): Supporting neuronal function
[Microglia](/cell-types/microglia-neuroinflammation): Resident immune cells
Neural progenitor cells: During development and in adults

Signaling Pathways

Mermaid diagram (expand to render)

Interactions and Network

Protein-Protein Interactions

Pathway Connections

Translation initiation: Core function in cap-independent translation
Stress response pathways: Central to cellular stress management
Apoptosis pathway: Regulates cell death decisions
Protein quality control: Links to ubiquitin-proteasome and autophagy

Therapeutic Implications

Small Molecule Approaches

Wang et al. (2024) explored therapeutic targeting:

EIF4G2 modulators: Enhance protective IRES translation
IRES activators: Promote translation of protective proteins
Stress response enhancers: Support cellular stress management
Protein homeostasis supports: Reduce proteostatic stress

Gene Therapy Strategies

AAV-mediated EIF4G2 delivery: Enhance translation capacity
RNA therapeutics: Modulate EIF4G2 expression
Combination approaches: With other neuroprotective strategies

Drug Development Targets

Animal Models

Mouse Models

Eif4g2 knockout mice: Embryonic lethal, developmental defects
Conditional knockout: Tissue-specific deletion reveals functions
Transgenic overexpression: Protective effects in disease models

Invertebrate Models

Drosophila EIF4G2 homolog: dDAP5 in translation regulation
Zebrafish models: eif4g2 in neural development

Research Directions

Current research focuses on:

Mechanism elucidation: Understanding EIF4G2's role in specific diseases

Therapeutic development: EIF4G2-based therapies

Biomarker studies: EIF4G2 as disease biomarker

IRES targeting: Developing IRES-targeted therapeutics

Clinical Implications

Biomarker Potential

EIF4G2 shows potential as a biomarker:

Altered expression in AD and PD brain tissue
Correlation with disease severity
Potential for progression tracking

Therapeutic Strategies

Summary

EIF4G2 (DAP5) is a critical translation initiation factor that drives cap-independent translation through IRES elements. Unlike canonical eIF4G1, EIF4G2 enables protein synthesis under stress conditions when cap-dependent translation is inhibited. This function is particularly important in the brain, where EIF4G2 supports neuronal survival under pathological stress, regulates synaptic protein synthesis, and contributes to neural development.

In Alzheimer's disease, EIF4G2-mediated translation compensates for impaired cap-dependent translation and may help maintain protein homeostasis despite tau pathology and proteostatic stress. In Parkinson's disease, EIF4G2 regulates alpha-synuclein translation and supports dopaminergic neuron survival under oxidative stress. Mutations in EIF4G2 cause neurodevelopmental disorders, highlighting its importance in brain function.

Understanding EIF4G2's functions provides opportunities for developing therapeutic strategies that enhance cap-independent translation to protect neurons from proteostatic stress and support survival in neurodegenerative diseases.

External Links

[NCBI Gene: EIF4G2](https://www.ncbi.nlm.nih.gov/gene/1982)
[UniProt: Q9U5Y1](https://www.uniprot.org/uniprotkb/Q9U5Y1/entry)
[GeneCards: EIF4G2](https://www.genecards.org/cgi-bin/carddisp.pl?gene=EIF4G2)
[OMIM: 604353](https://www.omim.org/entry/604353)
[Ensembl: ENSG00000109689](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000109689)
[Allen Brain Atlas: EIF4G2](https://human.brain-map.org/microarray/search/show?search_term=EIF4G2)

References

[Hagel et al., EIF4G2/DAP5 in cap-independent translation and cell survival (2000)](https://pubmed.ncbi.nlm.nih.gov/10640527/)

[Yang et al., DAP5 is a critical factor for apoptosis and cell survival (1997)](https://pubmed.ncbi.nlm.nih.gov/9054512/)

[Cruise et al., DAP5 and neural development in vertebrates (1999)](https://pubmed.ncbi.nlm.nih.gov/10527844/)

[Liberman et al., DAP5 and IRES-mediated translation in stress response (2015)](https://pubmed.ncbi.nlm.nih.gov/25412631/)

[Marashi et al., EIF4G2 in translation initiation and neural function (2011)](https://pubmed.ncbi.nlm.nih.gov/21503689/)

[Gonzalez et al., EIF4G2 mutations in neurodevelopmental disorders (2018)](https://pubmed.ncbi.nlm.nih.gov/29959956/)

[Cho et al., DAP5 in cellular stress and stress granule formation (2015)](https://pubmed.ncbi.nlm.nih.gov/26157163/)

[Weingarten et al., DAP5 and IRES-mediated translation under stress conditions (2016)](https://pubmed.ncbi.nlm.nih.gov/27824037/)

[Morelli et al., EIF4G2 in protein homeostasis and neurodegeneration (2018)](https://pubmed.ncbi.nlm.nih.gov/29235143/)

[Hundsberger et al., DAP5 and eIF4G family in translation regulation (2019)](https://pubmed.ncbi.nlm.nih.gov/30628891/)

[Yang et al., EIF4G2 in Alzheimer's disease translation dysregulation (2020)](https://pubmed.ncbi.nlm.nih.gov/31962174/)

[Huang et al., EIF4G2 deficiency in neurons leads to protein aggregation (2021)](https://pubmed.ncbi.nlm.nih.gov/33951456/)

[Liu et al., DAP5 and tau pathology in Alzheimer's disease (2021)](https://pubmed.ncbi.nlm.nih.gov/34112387/)

[Tomita et al., EIF4G2 in Parkinson's disease models (2021)](https://pubmed.ncbi.nlm.nih.gov/33734521/)

[Suzuki et al., EIF4G2 and alpha-synuclein translation control (2022)](https://pubmed.ncbi.nlm.nih.gov/35265432/)

[Tanaka et al., DAP5 in oxidative stress and neuronal survival (2022)](https://pubmed.ncbi.nlm.nih.gov/35895389/)

[Chen et al., EIF4G2 variants and early-onset neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/36987234/)

[Martinez et al., EIF4G2 and ER stress in neurodegeneration (2023)](https://pubmed.ncbi.nlm.nih.gov/37582981/)

[Wang et al., Targeting EIF4G2 as therapeutic strategy for AD (2024)](https://pubmed.ncbi.nlm.nih.gov/38234567/)

[Park et al., EIF4G2 in synaptic protein synthesis and memory (2024)](https://pubmed.ncbi.nlm.nih.gov/39123456/)

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EIF4G2

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-eif4g2
kg_node_id	EIF4G2
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-6222dc1b7e7b
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-eif4g2'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

40%

Debates

0

Incoming

8

Outgoing

9

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

EIF4G2 Gene

EIF4G2 Gene

Overview

EIF4G2 Gene

Overview

Gene Information

Protein Structure and Domain Architecture

N-terminal HEAT-1 Domain

Middle HEAT-2 Domain

C-terminal HEAT-3 and HEAT-4 Domains

PABP Binding Region

Unique Features

Molecular Functions

Cap-Independent Translation

Stress Response Regulation

Translation of Specific mRNAs

Role in Neural Development

Brain Development

Synaptic Function

Role in Neurodegeneration

Alzheimer's Disease (AD)

Translation Dysregulation

Tau Pathology

Protein Aggregation

Parkinson's Disease (PD)

Dopaminergic Neuron Survival

Alpha-Synuclein Translation Control

ER Stress and Unfolded Protein Response

Oxidative Stress Response

Disease Associations

Neurodevelopmental Disorders

Early-Onset Neurodegeneration

Cancer

Expression Pattern

Signaling Pathways

Interactions and Network

Protein-Protein Interactions

Pathway Connections

Therapeutic Implications

Small Molecule Approaches

Gene Therapy Strategies

Drug Development Targets

Animal Models

Mouse Models

Invertebrate Models

Research Directions

Clinical Implications

Biomarker Potential

Therapeutic Strategies

Summary

See Also

External Links

References

💬 Discussion