Unfolded protein response (UPR) machinery (UPR)

The endoplasmic reticulum (ER) stress machinery, primarily known as the unfolded protein response (UPR), is a complex signal transduction network that monitors and maintains the protein-folding capacity of the ER. It is governed by three main transmembrane sensors: Inositol-requiring enzyme 1 (IRE1), Protein kinase RNA-like endoplasmic reticulum kinase (PERK), and Activating transcription factor 6 (ATF6). Under normal conditions, these sensors are kept inactive by the chaperone BiP; however, the accumulation of misfolded proteins causes BiP to dissociate, triggering the UPR to expand ER capacity and reduce protein load. If the stress is chronic or overwhelming, the machinery transitions from an adaptive, pro-survival phase to a terminal, pro-apoptotic phase, often involving the upregulation of CHOP. In diseases like cancer, the UPR is frequently hijacked to support tumor survival under hypoxic and nutrient-deprived conditions, whereas in neurodegenerative diseases, chronic ER stress contributes to neuronal loss. Therapeutic interventions target specific components of this machinery, such as PERK or IRE1 inhibitors to sensitize tumors, or chemical chaperones like 4-phenylbutyric acid to alleviate stress in metabolic disorders (Source: NIH, PubMed, UniProt).

Other names

Endoplasmic reticulum stress responseER stress machineryERSRIntracellular signaling pathway of the endoplasmic reticulum

Modulation of the three primary signaling arms (PERK, IRE1, and ATF6) to either restore endoplasmic reticulum proteostasis or induce programmed cell death in stressed cells.