Endoplasmic reticulum stress machinery (ER stress machinery)

The Endoplasmic Reticulum (ER) stress machinery, primarily mediated by the Unfolded Protein Response (UPR), is a complex signaling network that monitors and maintains protein folding quality control within the ER (Hetz et al., 2020). It is activated when the demand for protein folding exceeds the ER's capacity, leading to the accumulation of misfolded proteins (Wang & Kaufman, 2016). The machinery is governed by three primary transmembrane sensors: Inositol-requiring enzyme 1 (IRE1), Protein kinase RNA-like endoplasmic reticulum kinase (PERK), and Activating transcription factor 6 (ATF6) (Oakes & Papa, 2015). Under mild stress, these sensors trigger adaptive responses to restore homeostasis; however, chronic or severe stress shifts the signaling toward programmed cell death (apoptosis) (Hetz et al., 2020). Dysregulation of this machinery is a hallmark of various pathologies, including cancer, where it promotes tumor survival, and neurodegeneration, where it contributes to neuronal loss (Oakes & Papa, 2015). Therapeutic strategies involve small molecules that either inhibit specific UPR sensors to sensitize cancer cells or act as chemical chaperones to alleviate stress in metabolic and degenerative diseases (Hetz et al., 2019).

Other names

Unfolded Protein Response (UPR)ER stress responseProteostasis networkER quality control system

Modulation of the unfolded protein response (UPR) sensors (IRE1, PERK, ATF6) to either restore proteostasis or induce apoptosis in stressed cells.