The integrated stress response

A scoped project: about 18 candidate genes, five already reviewed

AI Gene Review · projects/INTEGRATED_STRESS_RESPONSE · 2026

Bottom line

  • Four kinases (HRI, PKR, PERK, GCN2) each sense a different stress and phosphorylate eIF2α, which blocks eIF2B, dampens translation and lets ATF4 through.
  • Scoped, not yet started: no project-specific review work has been done.
  • 5 of 18 candidates already have reviews from other work (EIF2AK3, ATF4, ATF3, EIF2B4 COMPLETE; OMA1 IN_PROGRESS; 489 annotations). EIF2S1, three kinases and DELE1 have no gene folder.

Four sensors, one switch

Why this pathway

  • A drug target: ISRIB binds a cleft in the eIF2B decamer (cryo-EM structure cited in the EIF2B4 review).
  • eIF2B mutations cause vanishing white matter disease.
  • The DELE1-HRI route from mitochondrial stress was described only in 2020, so GO may not yet reflect it.
  • Clear convergence: four kinases → one substrate → one exchange factor → one transcription factor.

An existing review: EIF2AK3 (PERK)

Generic kinase rows are MODIFY'd to eukaryotic translation initiation factor 2alpha kinase activity; ISR involvement is carried by the accepted PERK-mediated unfolded protein response (GO:0036499); a NEW integrated stress response signaling (GO:0140467) row, its ancestor, was dropped in PR #3219.

Status and next steps

Genes State
EIF2AK3 (95 ann.), ATF4 (216), ATF3 (80), EIF2B4 (44) COMPLETE
OMA1 (54) IN_PROGRESS
EIF2AK1, EIF2AK2, EIF2AK4, EIF2S1, DELE1, DDIT3, PPP1R15A, PPP1R15B, EIF2B1/2/3/5, ASNS No gene folder
  • ⬜ just fetch-gene human <GENE>, starting with EIF2S1, the other three kinases and DELE1.
  • ⬜ An ISR module once the core is reviewed.

Read more: projects/INTEGRATED_STRESS_RESPONSE.md