Integrated Stress Response (ISR) Project
Bottom line: in the integrated stress response, four kinases (HRI, PKR,
PERK and GCN2) each sense a different stress and phosphorylate eIF2α, which
blocks the eIF2B exchange factor, dampens global translation and lets ATF4 be
translated. Scoped, not yet started as a project: this page lists about 18
candidate human genes, including the DELE1-OMA1 route from mitochondrial stress
to HRI, but no project-specific review work has been done. Five candidates
already have reviews from other work: EIF2AK3 (PERK), ATF4, ATF3 and EIF2B4 are
COMPLETE and OMA1 is IN_PROGRESS, 489 annotations between them. Thirteen have
no gene folder, including the hub EIF2S1 (eIF2α), three of the four kinases,
DELE1 and four of the five eIF2B subunits. There is no ISR module yet.
We scoped this because the ISR is a drug target (ISRIB), eIF2B mutations cause
vanishing white matter disease, and the DELE1-HRI branch was only described in
2020, so current GO annotation may not reflect it.
Overview
The Integrated Stress Response (ISR) is a conserved signaling pathway that responds to diverse cellular stresses by phosphorylating eIF2α, leading to global translation attenuation and selective translation of stress-response genes like ATF4. Recent discoveries include the DELE1-HRI mitochondrial stress pathway.
Model Species
Primary: Homo sapiens (human)
- Therapeutic target (ISRIB and related compounds)
- Disease relevance across multiple conditions
Core Pathway Architecture
1. eIF2α Kinases (Stress Sensors)
Four kinases sense different stresses:
- EIF2AK1 (HRI) - Heme deficiency, mitochondrial stress
- EIF2AK2 (PKR) - Viral dsRNA
- EIF2AK3 (PERK) - ER stress
- EIF2AK4 (GCN2) - Amino acid starvation
2. Mitochondrial Stress Signaling (New!)
- DELE1 - Mitochondrial stress sensor, activates HRI
- OMA1 - Protease that cleaves DELE1
3. Core Pathway
- EIF2S1 (eIF2α) - Translation initiation factor, phosphorylation target
- EIF2B1-5 - eIF2B complex, guanine nucleotide exchange factor
- PPP1R15A (GADD34) - Phosphatase regulatory subunit, negative feedback
- PPP1R15B (CReP) - Constitutive phosphatase
4. Transcriptional Response
- ATF4 - Master ISR transcription factor
- DDIT3 (CHOP) - Pro-apoptotic TF
- ATF3 - Stress-responsive TF
- ASNS - ATF4 target gene (asparagine synthetase)
Candidate Genes (~18)
| Gene | UniProt | Function |
|---|---|---|
| EIF2AK1 | Q9BQI3 | HRI kinase |
| EIF2AK2 | P19525 | PKR kinase |
| EIF2AK3 | Q9NZJ5 | PERK kinase |
| EIF2AK4 | Q9P2K8 | GCN2 kinase |
| EIF2S1 | P05198 | eIF2α |
| DELE1 | Q14154 | Mitochondrial sensor |
| OMA1 | Q96E52 | DELE1 protease |
| ATF4 | P18848 | Master TF |
| DDIT3 | P35638 | CHOP |
| PPP1R15A | O75807 | GADD34 |
| PPP1R15B | Q5SWA1 | CReP |
| EIF2B1-5 | various | eIF2B complex |
Key Recent Discoveries (2020+)
- DELE1-HRI pathway for mitochondrial stress (2020)
- ISRIB mechanism of action
- ISR in aging and neurodegeneration
- COVID-19 and ISR activation
Disease Relevance
- Vanishing white matter disease (EIF2B mutations)
- Neurodegeneration
- Cancer (stress adaptation)
- Metabolic disease
Project Status
- [ ] Stub - needs gene folder setup
- EIF2AK3 (PERK): the review does not add GO:0140467 integrated stress
response signaling. PR #3219
removed that proposedNEWrow: GO:0140467 is an ancestor of the
already-accepted GO:0036499 PERK-mediated unfolded protein response, and
the cited 1999 cloning paper (PMID:9930704) does not show ISR signalling.
With #3219 merged, EIF2AK3 has 95 annotation rows, down from 96.
Slides
- Slides (Marp source: INTEGRATED_STRESS_RESPONSE-slides.md) — AI generated