Unfolded protein response (UPR) (UPR)

The Unfolded Protein Response (UPR) is a complex intracellular signaling network activated by the accumulation of misfolded proteins in the endoplasmic reticulum (ER) lumen (Hetz et al., 2020, Nature Reviews Cancer). It is governed by three primary sensors: Inositol-requiring enzyme 1 (IRE1α), Protein kinase RNA-like endoplasmic reticulum kinase (PERK), and Activating transcription factor 6 (ATF6) (Walter & Ron, 2011, Science). Under homeostatic conditions, these sensors are kept inactive by the chaperone BiP, but they dissociate and activate upon sensing unfolded proteins (Wang & Kaufman, 2016, Nature). The initial adaptive phase of the UPR aims to restore ER capacity by expanding ER volume, increasing chaperone expression, and degrading misfolded proteins via ER-associated degradation (ERAD) (Hetz et al., 2020, Nature Reviews Cancer). If ER stress persists, the UPR switches to a terminal phase that triggers apoptosis, often through the induction of CHOP and JNK signaling (Marciniak et al., 2004, Genes & Development). In oncology, many tumors exploit the UPR to survive harsh microenvironments, making UPR components attractive targets for small molecule inhibitors (Oakes, 2020, American Journal of Pathology). Conversely, in neurodegenerative diseases like Alzheimer's and Parkinson's, chronic UPR activation contributes to neuronal loss, suggesting that UPR modulators could be neuroprotective (Halliday et al., 2017, Brain). Therapeutic agents currently include chemical chaperones like 4-phenylbutyric acid and specific inhibitors of the IRE1α or PERK branches (Kim et al., 2021, Molecules and Cells).

Other names

ER stress responseEndoplasmic reticulum stress pathwayER stress-induced signalingEndoplasmic reticulum stress response

Inhibition of IRE1α endoribonuclease activity, inhibition of PERK kinase activity, chemical chaperone-mediated protein stabilization, and modulation of the integrated stress response.