response to endoplasmic reticulum stress

Definition

Target type: biologicalprocess

Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stress acting at the endoplasmic reticulum. ER stress usually results from the accumulation of unfolded or misfolded proteins in the ER lumen. [GOC:cjm, GOC:mah]

The endoplasmic reticulum (ER) is a cellular organelle responsible for protein folding, modification, and trafficking. When the ER encounters stress, such as misfolded proteins, oxidative stress, or nutrient deprivation, it triggers a complex signaling pathway known as the unfolded protein response (UPR). The UPR aims to restore ER homeostasis by reducing protein synthesis, increasing protein folding capacity, and eliminating misfolded proteins. The UPR is mediated by three transmembrane sensors: PERK, IRE1, and ATF6.

* **PERK** (PKR-like ER kinase) is activated by unfolded proteins in the ER lumen. Activated PERK phosphorylates eIF2α, a key component of the translation initiation complex, leading to a global reduction in protein synthesis. This alleviates ER stress by reducing the load of newly synthesized proteins that need to be folded.
* **IRE1** (inositol-requiring enzyme 1) is another ER transmembrane kinase that is activated by unfolded proteins. Upon activation, IRE1 oligomerizes and its endoribonuclease activity is stimulated. IRE1 splices XBP1 mRNA, which encodes a transcription factor that activates genes involved in ER protein folding, ER-associated degradation (ERAD), and lipid biosynthesis.
* **ATF6** (activating transcription factor 6) is a transcription factor that resides in the ER membrane. Upon ER stress, ATF6 translocates to the Golgi apparatus, where it is cleaved by proteases. The cleaved ATF6 fragment enters the nucleus and activates genes involved in ER chaperone production and lipid biosynthesis.

The UPR is a finely tuned signaling pathway that involves a complex interplay between these three sensors. The specific response to ER stress depends on the severity and duration of the stress, as well as the cell type. In mild stress, the UPR can restore ER homeostasis and maintain cell viability. However, if the stress is prolonged or severe, the UPR can trigger apoptosis, a programmed cell death mechanism.

The UPR plays a critical role in maintaining cell health and is implicated in various disease processes, including cancer, neurodegenerative disorders, and diabetes. Understanding the UPR pathway is essential for developing therapeutic strategies for these diseases.'
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Proteins (24)

Compounds (2,150)