Category: signaling
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).