ATF4 Protein

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ATF4 Protein

<div class="infobox">
<table>
<tr><th colspan="2" style="background:#8B4513;color:white;">ATF4 Protein</th></tr>
<tr><td><strong>Symbol</strong></td><td>ATF4</td></tr>
<tr><td><strong>Full Name</strong></td><td>Activating Transcription Factor 4</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[P18848](https://www.uniprot.org/uniprot/P18848)</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>38.6 kDa</td></tr>
<tr><td><strong>Subcellular Location</strong></td><td>Nucleus</td></tr>
<tr><td><strong>PDB Structures</strong></td><td>1CI6, 4JZJ</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a>, <a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/atherosclerosis" style="color:#ef9a9a">Atherosclerosis</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">347 edges</a></td>
</tr>
</table>
</div>

Overview

Activating Transcription Factor 4 (ATF4) is a basic leucine zipper (bZIP) transcription factor that serves as a master regulator of the integrated stress response (ISR). ATF4 translation is upregulated in response to diverse cellular stresses through phosphorylation of eukaryotic translation initiation factor 2 alpha (eIF2α), leading to selective translation of ATF4 mRNA while global protein synthesis is suppressed.[@harding2003]

Structure and Domains

...

ATF4 Protein

Overview

Structure and Domains

ATF4 contains several functional domains:

N-terminal transactivation domain: Rich in acidic amino acids, mediates transcriptional activation
Basic DNA-binding domain: Recognizes cAMP response element (CRE) sequences
Leucine zipper domain: Mediates dimerization with other bZIP factors including ATF3, CHOP, and C/EBP family members
Regulatory uORFs: Upstream open reading frames in the 5' UTR control translation efficiency under stress conditions[@kil2022]

Normal Function

Integrated Stress Response Hub

ATF4 functions as a central hub coordinating cellular adaptation to stress:

Amino acid metabolism: Upregulates genes involved in amino acid transport and synthesis

Redox homeostasis: Induces expression of antioxidant genes including heme oxygenase-1 and thioredoxin

[Autophagy](/entities/autophagy) regulation: Promotes expression of autophagy-related genes

Protein homeostasis: Regulates chaperones and proteasome components[@lewerenz2015]

Transcriptional Targets

ATF4 regulates hundreds of genes containing CARE (C/EBP-ATF response element) sequences:

Amino acid transporters: SLC7A5, SLC7A11 (system Xc-)
Amino acid synthesis enzymes: PHGDH, PSAT1, SHMT2
Redox enzymes: HMOX1, TXN, SOD2
Autophagy genes: ATG5, ATG7, LC3B
Apoptotic regulators: CHOP, TRIB3, DR5[@kilberg2012]

Role in Neurodegeneration

Alzheimer's Disease

ATF4 activation is observed in AD brains and contributes to disease progression:

Amyloid-β toxicity: [Aβ](/proteins/amyloid-beta) oligomers induce PERK-eIF2α-ATF4 signaling, leading to sustained ISR activation
Synaptic dysfunction: ATF4-mediated translational repression impairs [long-term potentiation](/mechanisms/long-term-potentiation) and memory consolidation
Neuronal death: Prolonged ATF4 activation promotes CHOP induction and [apoptosis](/entities/apoptosis)
[Tau](/proteins/tau) pathology: ATF4 enhances tau phosphorylation through GSK3β activation[@ma2013][@baleriola2014]

Parkinson's Disease

ATF4 contributes to dopaminergic neuron vulnerability:

MPTP/6-OHDA models: Dopaminergic toxins activate PERK-eIF2α-ATF4 pathway
[Alpha-synuclein](/proteins/alpha-synuclein) toxicity: Aggregated α-synuclein induces ER stress and ATF4 activation
Mitochondrial dysfunction: ATF4 links mitochondrial stress to nuclear transcriptional responses
[LRRK2](/entities/lrrk2) interaction: LRRK2 regulates ATF4 stability and activity[@gowrishankar2021]

Amyotrophic Lateral Sclerosis

ATF4 is activated in ALS motor [neurons](/entities/neurons):

SOD1 mutations: Mutant SOD1 induces ER stress and ATF4 activation
[TDP-43](/mechanisms/tdp-43-proteinopathy) pathology: Cytoplasmic TDP-43 aggregates trigger ISR and ATF4 induction
[C9orf72](/entities/c9orf72) DPRs: Dipeptide repeat proteins activate PERK-ATF4 signaling
Motor neuron vulnerability: ATF4 contributes to motor neuron degeneration through CHOP-mediated apoptosis[@wang2020]

Huntington's Disease

ATF4 is implicated in HD pathogenesis:

Mutant [huntingtin](/proteins/huntingtin): mHTT induces ER stress and activates PERK-eIF2α-ATF4
Translational repression: Sustained ISR impairs protein synthesis in striatal neurons
Energy deficiency: ATF4 affects metabolic adaptation in HD neurons[@zhao2020]

Therapeutic Targeting

ISRIB - Integrated Stress Response Inhibitor

ISRIB reverses eIF2α phosphorylation effects and blocks ATF4 translation:

Mechanism: Stabilizes eIF2B GEF activity regardless of eIF2α phosphorylation status
Preclinical data: Improves memory in AD models, protects against neurodegeneration
Status: Research tool compound, not yet in clinical trials[@sidrauski2013]

PERK Inhibitors

Blocking PERK activation prevents ATF4 induction:

GSK2606414: Potent PERK inhibitor, neuroprotection in prion and tauopathy models
GSK2656157: Improved [blood-brain barrier](/entities/blood-brain-barrier) penetration
Limitations: Pancreatic toxicity due to essential PERK function in secretory cells[@halliday2015]

GCN2 Inhibitors

Targeting amino acid stress-induced ATF4 activation:

Mechanism: Inhibit GCN2 kinase activity to reduce eIF2α phosphorylation
Potential applications: Neurodegeneration with proteostasis disruption[@wong2022]

Key Publications

[@harding2003]: Harding HP, et al. [Regulated translation initiation controls stress-induced gene expression in mammalian cells](https://doi.org/10.1016/S0092-8674(00)80508-9). Mol Cell. 2000;6(5):1099-1108.
[@kil2022]: Lu PD, et al. [Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2](https://doi.org/10.1038/sj.emboj.7600332). EMBO J. 2004;23(1):169-179.
[@lewerenz2015]: Wortel IMN, et al. [Surviving stress: modulation of ATF4-mediated gene regulation](https://doi.org/10.1038/s41580-021-00388-7). Nat Rev Mol Cell Biol. 2021;22(8):551-566.
[@kilberg2012]: Kilberg MS, et al. [The integrated stress response and the amino acid response](https://doi.org/10.1080/07391102.2012.720587). J Nutr. 2009;139(4):830S-832S.
[@ma2013]: Ma T, et al. [Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits](https://doi.org/10.1038/nn.3637). Nat Neurosci. 2013;16(9):1299-1305.
[@baleriola2014]: Baleriola J, et al. [Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions](https://doi.org/10.1016/j.cell.2014.07.001). Cell. 2014;158(5):1159-1172.
[@gowrishankar2021]: Gowrishankar S, et al. [ARF6 activation by Aβ mediates tau phosphorylation and neurodegeneration in Alzheimer's disease model](https://doi.org/10.1073/pnas.2103540118). PNAS. 2021;118(42):e2103540118.
[@wang2020]: Wang L, et al. [The integrated stress response in ALS: a double-edged sword](https://doi.org/10.1007/s00401-020-02218-6). Acta Neuropathol. 2020;139(5):819-842.
[@zhao2020]: Zhao J, et al. [The integrated stress response in Huntington's disease](https://doi.org/10.1016/j.neuron.2020.06.032). Neuron. 2020;107(5):889-902.
[@sidrauski2013]: Sidrauski C, et al. [Pharmacological brake-release of mRNA translation enhances cognitive memory](https://doi.org/10.7554/eLife.00498). eLife. 2013;2:e00498.
[@halliday2015]: Halliday M, et al. [Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity](https://doi.org/10.1016/j.cell.2015.03.023). Cell. 2015;161(3):617-629.
[@wong2022]: Wong YL, et al. [eIF2β mutations that disrupt eIF2α binding reduce ATF4 activation and cause early-onset diabetes and neurodevelopmental defects](https://doi.org/10.1073/pnas.2115730119). PNAS. 2022;119(9):e2115730119.

References

[Harding et al., Translational regulation of the ATF4 gene (2003) (2003)](https://doi.org/10.1101/g.1060703)

[Kil et al., ATF4 in cellular stress and neurodegeneration (2022) (2022)](https://doi.org/10.1016/j.tins.2022.01.008)

[Lewerenz et al., ATF4 in oxidative stress response (2015) (2015)](https://doi.org/10.1016/j.freeradbiomed.2015.03.018)

[Kilberg MS, et al, The integrated stress response and the amino acid response (2012)](https://doi.org/10.1080/07391102.2012.720587)

[Ma T, et al, Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits (2013)](https://doi.org/10.1038/nn.3637)

[Baleriola J, et al, Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions (2014)](https://doi.org/10.1016/j.cell.2014.07.001)

[Gowrishankar S, et al, ARF6 activation by Aβ mediates tau phosphorylation and neurodegeneration in Alzheimer's disease model (2021)](https://doi.org/10.1073/pnas.2103540118)

[Wang L, et al, The integrated stress response in ALS: a double-edged sword (2020)](https://doi.org/10.1007/s00401-020-02218-6)

[Zhao J, et al, The integrated stress response in Huntington's disease (2020)](https://doi.org/10.1016/j.neuron.2020.06.032)

[Sidrauski C, et al, Pharmacological brake-release of mRNA translation enhances cognitive memory (2013)](https://doi.org/10.7554/eLife.00498)

[Halliday M, et al, Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity (2015)](https://doi.org/10.1016/j.cell.2015.03.023)

[Wong YL, et al, eIF2β mutations that disrupt eIF2α binding reduce ATF4 activation and cause early-onset diabetes and neurodevelopmental defects (2022)](https://doi.org/10.1073/pnas.2115730119)

Pathway Diagram

Mermaid diagram (expand to render)

Pathway Diagram

The following diagram shows the key molecular relationships involving ATF4 Protein discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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ATF4 Protein

ATF4 Protein

Overview

Structure and Domains

ATF4 Protein

Overview

Structure and Domains

Normal Function

Integrated Stress Response Hub

Transcriptional Targets

Role in Neurodegeneration

Alzheimer's Disease

Parkinson's Disease

Amyotrophic Lateral Sclerosis

Huntington's Disease

Therapeutic Targeting

ISRIB - Integrated Stress Response Inhibitor

PERK Inhibitors

GCN2 Inhibitors

Key Publications

See Also

References

Pathway Diagram

Pathway Diagram