Page last updated: 2024-10-24

endoplasmic reticulum stress-induced pre-emptive quality control

Definition

Target type: biologicalprocess

The response to endoplasimic reticulum stress in which nascent proteins are degraded by attenuation of their translocation into the ER followed by rerouting to the cytosol without cleavage of the signal peptide, and subsequent degradation by the proteasome. [PMID:17129784, PMID:26565908]

Endoplasmic reticulum (ER) stress-induced pre-emptive quality control is a sophisticated cellular mechanism that anticipates and mitigates potential protein folding problems before they arise. This anticipatory quality control system operates within the ER, a cellular organelle responsible for the synthesis and folding of proteins destined for secretion or for insertion into cellular membranes.

The ER is a dynamic environment where the folding of nascent polypeptides into their functional conformations is a continuous process. However, various factors, including nutrient deprivation, hypoxia, viral infection, and accumulation of misfolded proteins, can disrupt ER homeostasis, leading to a condition known as ER stress.

When ER stress occurs, the cell activates a complex signaling pathway known as the unfolded protein response (UPR). The UPR aims to restore ER homeostasis by attenuating protein translation, enhancing protein folding capacity, and promoting degradation of misfolded proteins. However, if ER stress persists, the UPR can trigger apoptosis, a programmed cell death mechanism, to eliminate severely compromised cells.

Pre-emptive quality control, as the name suggests, operates proactively to prevent the accumulation of misfolded proteins in the ER. This strategy involves a multi-layered approach:

1. **Attenuation of Protein Synthesis:** Upon detecting ER stress, the UPR signals the translational machinery to reduce protein synthesis. This decrease in protein load reduces the burden on the ER, giving it time to cope with the existing misfolded proteins.

2. **Enhancement of Protein Folding Capacity:** The UPR upregulates the expression of chaperone proteins like BiP/GRP78 and protein disulfide isomerase (PDI). These chaperones assist in protein folding, ensuring that newly synthesized proteins adopt their correct conformations.

3. **ERAD (ER-associated Degradation):** The UPR promotes the degradation of misfolded proteins via the ER-associated degradation (ERAD) pathway. This pathway involves retrotranslocation of misfolded proteins from the ER lumen into the cytoplasm, where they are ubiquitinated and subsequently degraded by the proteasome.

4. **ER Expansion:** To accommodate the increased protein folding demand, the UPR induces the expansion of the ER membrane. This provides additional space and resources for protein folding and quality control.

5. **Autophagy:** In severe cases of ER stress, the UPR can initiate autophagy, a cellular process that degrades damaged organelles, including the ER itself. Autophagy removes the source of misfolded proteins and recycles their components.

The pre-emptive quality control mechanism allows cells to anticipate and mitigate potential protein folding problems, ensuring efficient protein synthesis and cellular function. By reducing the accumulation of misfolded proteins, this anticipatory system plays a crucial role in preventing ER stress-induced cell death. The intricate interplay of these pathways exemplifies the remarkable resilience and adaptability of cellular systems in response to stress.'
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Proteins (1)

ProteinDefinitionTaxonomy
Transitional endoplasmic reticulum ATPaseA transitional endoplasmic reticulum ATPase that is encoded in the genome of human. [PRO:DNx, UniProtKB:P55072]Homo sapiens (human)

Compounds (6)

CompoundDefinitionClassesRoles
clotrimazoleconazole antifungal drug;
imidazole antifungal drug;
imidazoles;
monochlorobenzenes
antiinfective agent;
environmental contaminant;
xenobiotic
Methylenedioxycinnamic acidhydroxycinnamic acid
3,4-methylenedioxy-beta-nitrostyrene3,4-methylenedioxy-beta-nitrostyrene: tyrosine kinase inhibitor that prevents platelet glycoprotein IIb/IIIa activation; structure in first source
4-(4-(4-chloro-phenyl)thiazol-2-ylamino)phenolsubstituted aniline
ML240ML240 : A member of the class of quinazolines that is quinazoline which is substituted at positions 2, 5 and 8 by 2-amino-1H-benzimidazol-1-yl, benzylnitrilo and methoxy groups, respectively. It is a ATP-competetive inhibitor of AAA ATPase p97, also known as valosin-containing protein (VCP).aromatic amine;
aromatic ether;
benzimidazoles;
primary amino compound;
quinazolines;
secondary amino compound
antineoplastic agent
ganciclovir2-aminopurines;
oxopurine
antiinfective agent;
antiviral drug