Intracellular signaling pathways and ER stress machinery (Unfolded Protein Response) (UPR)

The intracellular signaling pathways and ER stress machinery, primarily referred to as the Unfolded Protein Response (UPR), comprise a complex signal transduction network essential for maintaining protein folding quality control in the endoplasmic reticulum (ER). This system is governed by three key transmembrane sensors: Inositol-requiring enzyme 1 (IRE1), Protein kinase RNA-like endoplasmic reticulum kinase (PERK), and Activating transcription factor 6 (ATF6) (Source: Walter & Ron, Science, 2011). Under conditions of ER stress, these sensors activate downstream effectors to expand ER capacity, decrease protein translation, and enhance the degradation of misfolded proteins via ER-associated degradation (ERAD) (Source: Hetz et al., Nature Reviews Molecular Cell Biology, 2020). Chronic activation of these pathways is a hallmark of various pathologies, including cancer, where it supports tumor survival under metabolic stress, and neurodegenerative diseases like Alzheimer's and Parkinson's, where it may eventually trigger pro-apoptotic signaling through the induction of CHOP (Source: Wang & Kaufman, Nature, 2016). Pharmacological modulation of this machinery involves chemical chaperones to assist folding or small-molecule inhibitors/activators of specific UPR branches to alter cell fate in disease contexts (Source: Halliday et al., Brain, 2017).

Other names

Unfolded Protein ResponseER Stress ResponseProteostasis NetworkER-associated degradation pathway

Modulation of the Unfolded Protein Response (UPR) sensors (IRE1, PERK, ATF6) to either restore ER proteostasis or induce terminal apoptosis.