| ATF4 Protein | |
|---|---|
| Symbol | ATF4 |
| Full Name | Activating Transcription Factor 4 |
| UniProt ID | [P18848](https://www.uniprot.org/uniprot/P18848) |
| Molecular Weight | 38.6 kDa |
| Subcellular Location | Nucleus |
| PDB Structures | 1CI6, 4JZJ |
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.[1]
ATF4 contains several functional domains:
ATF4 functions as a central hub coordinating cellular adaptation to stress:
ATF4 regulates hundreds of genes containing CARE (C/EBP-ATF response element) sequences:
ATF4 activation is observed in AD brains and contributes to disease progression:
ATF4 contributes to dopaminergic neuron vulnerability:
ATF4 is activated in ALS motor neurons:
ATF4 is implicated in HD pathogenesis:
ISRIB reverses eIF2α phosphorylation effects and blocks ATF4 translation:
Blocking PERK activation prevents ATF4 induction:
Targeting amino acid stress-induced ATF4 activation:
Harding et al. Translational regulation of the ATF4 gene (2003). 2003. ↩︎
Kil et al. ATF4 in cellular stress and neurodegeneration (2022). 2022. ↩︎
Lewerenz et al. ATF4 in oxidative stress response (2015). 2015. ↩︎
Kilberg MS, et al. The integrated stress response and the amino acid response. J Nutr. 2012. ↩︎
Ma T, et al. Suppression of eIF2α kinases alleviates Alzheimer's disease-related plasticity and memory deficits. Nat Neurosci. 2013. ↩︎
Baleriola J, et al. Axonally synthesized ATF4 transmits a neurodegenerative signal across brain regions. Cell. 2014. ↩︎
Gowrishankar S, et al. ARF6 activation by Aβ mediates tau phosphorylation and neurodegeneration in Alzheimer's disease model. PNAS. 2021. ↩︎
Wang L, et al. The integrated stress response in ALS: a double-edged sword. Acta Neuropathol. 2020. ↩︎
Zhao J, et al. The integrated stress response in Huntington's disease. Neuron. 2020. ↩︎
Sidrauski C, et al. Pharmacological brake-release of mRNA translation enhances cognitive memory. eLife. 2013. ↩︎
Halliday M, et al. Partial restoration of protein synthesis rates by the small molecule ISRIB prevents neurodegeneration without pancreatic toxicity. Cell. 2015. ↩︎
Wong YL, et al. eIF2β mutations that disrupt eIF2α binding reduce ATF4 activation and cause early-onset diabetes and neurodevelopmental defects. PNAS. 2022. ↩︎