The unfolded protein response (UPR) is the ER's quality-control system for accumulated misfolded proteins — triggered by accumulation that exceeds chaperone (BiP/GRP78) capacity. BiP normally binds the luminal domains of three ER-resident sensors (PERK, IRE1α, ATF6), keeping them inactive. When misfolded proteins accumulate, BiP is competed away → sensor activation. Three parallel arms: (1) PERK (PERK/EIF2AK3) — autophosphorylates → phosphorylates eIF2α → halts cap-dependent translation globally (reduces ER load) but selectively allows translation of ATF4 (because of uORFs) → induces CHOP, GADD34, amino-acid metabolism genes; sustained PERK → CHOP → apoptosis. (2) IRE1α — RNase + kinase; autophosphorylates → splices XBP1 mRNA (removes 26-nt intron) → XBP1s (spliced, active TF) → induces ER chaperones (BiP, GRP94), ERAD components, lipid biosynthesis. IRE1α also performs regulated IRE1-dependent decay (RIDD) of select mRNAs. (3) ATF6 — translocates to Golgi → cleaved by S1P/S2P proteases (same that cleave SREBPs) → cytosolic fragment (ATF6f) is a bZIP TF → induces BiP, XBP1, ERAD components. Acute UPR: pro-survival (restore homeostasis). Chronic/excessive UPR: pro-apoptotic (CHOP, JNK, caspase-12 in rodents). Disease relevance: type 2 diabetes (β-cell ER stress under chronic insulin demand); neurodegeneration (ALS, Parkinson, Alzheimer — protein aggregation triggers UPR); cancer (tumors co-opt IRE1/XBP1 for survival; hypoxia → UPR); cystic fibrosis (ΔF508 misfolding); transthyretin amyloidosis. Therapeutics: 4-phenylbutyrate + TUDCA — chemical chaperones (clinical for CF, urea-cycle disorders); ISRIB (integrated stress response inhibitor — PERK arm); GSK2606414 / GSK2656157 — PERK inhibitors (preclinical); ORIN1001 / MKC-3946 — IRE1 RNase inhibitors. Proteasome inhibitors (bortezomib) overload ERAD → ER stress → multiple myeloma cell death. Cross-links: apoptosis bcl2 axis (CHOP-driven), autophagy lc3 axis (UPR triggers autophagy), insulin glucose homeostasis (β-cell ER stress).
Organ Systems
immune-hematologic
digestive
endocrine
nervous
Pathway Steps
misfolded protein accumulation in ER lumen → BiP/GRP78 displacement from PERK / IRE1α / ATF6 — via BiP preferentially binds exposed hydrophobic stretches; sensors de-repressed. The UPR fires when misfolded proteins accumulate in the ER and titrate the chaperone BiP/GRP78 away from the three sensors PERK, IRE1α, and ATF6. Losing BiP activates all three arms — making BiP occupancy the master gauge of ER folding load and the UPR a homeostatic response to restore it.
PERK active → eIF2α phosphorylation → global translation arrest — via reduces ER load; selectively spares ATF4 mRNA via uORFs. The PERK arm phosphorylates eIF2α, halting most cap-dependent translation — rapidly reducing the protein load entering the stressed ER. This is the same eIF2α node used by the integrated stress response, linking ER stress to amino-acid, heme, and viral stress signals.
ATF4 → CHOP + GADD34 + amino-acid response genes — via GADD34 = PP1-targeting subunit → dephosphorylates eIF2α → feedback restart. Paradoxically, eIF2α phosphorylation favors translation of ATF4, which induces amino-acid/redox genes, GADD34 (a feedback phosphatase reversing the eIF2α block), and CHOP. ATF4-CHOP thus both aids recovery and, if stress persists, primes cell death.
IRE1α RNase → XBP1 splicing (26-nt intron removal) — via XBP1s = ER chaperones, ERAD, lipid synthesis; IRE1 also performs RIDD. The IRE1α arm is an endoribonuclease that excises a 26-nt intron from XBP1 mRNA; the spliced form encodes a potent transcription factor driving chaperone and ER-associated degradation (ERAD) genes. This most conserved UPR arm expands folding and disposal capacity to clear the backlog.
ATF6 (ER) → Golgi → S1P/S2P cleavage → ATF6f — via cytosolic ATF6f bZIP-TF → BiP, XBP1 transcription. When released, the ATF6 arm traffics to the Golgi, where S1P/S2P proteases cleave it to liberate the active transcription factor ATF6f. ATF6f induces chaperones and ERAD components, complementing XBP1 — together expanding the ER’s capacity to fold and degrade proteins.
sustained UPR (chronic) → CHOP-driven apoptosis — via pro-survival → pro-apoptotic switch when ER stress unresolved. If stress is unresolvable, the UPR switches from adaptive to terminal: sustained CHOP tips the balance to apoptosis (lowering BCL-2, raising pro-apoptotic BH3 proteins, and driving oxidative ER stress). This life/death switch links chronic ER stress to neurodegeneration, diabetes, and other diseases.
Known Modulators
metformin (inhibitor) — UPR (chronic; via AMPK-mediated ER stress reduction)