ATF4 Protein

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

<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 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:

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.

See Also

• [PERK](/proteins/perk) — [UPR](/entities/unfolded-protein-response) sensor kinase
• [EIF2α](/proteins/eif2a) — Translation initiation factor
• [CHOP](/proteins/chop) — ATF4 target and pro-apoptotic factor
• [Integrated Stress Response](/mechanisms/integrated-stress-response) — Pathway overview
• [Endoplasmic Reticulum Stress](/mechanisms/er-stress-pathway) — Cellular stress pathway

References

Pathway Diagram

Pathway Diagram

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