Unfolded protein response

Unfolded Protein Response

The unfolded protein response (UPR) is a cellular stress response related to the endoplasmic reticulum (ER). The UPR is activated in response to an accumulation of unfolded proteins in the ER lumen. This response aims to restore normal function by halting protein translation, degrading misfolded proteins, and activating the signaling pathways that lead to increased production of molecular chaperones involved in protein folding.

Mechanism

The UPR is initiated by three primary ER membrane-associated sensors: IRE1 (inositol-requiring enzyme 1), PERK (protein kinase RNA-like ER kinase), and ATF6 (activating transcription factor 6). These sensors detect the presence of unfolded or misfolded proteins in the ER and initiate downstream signaling pathways to mitigate the stress.

IRE1 Pathway

IRE1 is a transmembrane kinase/endoribonuclease that, upon activation, splices XBP1 (X-box binding protein 1) mRNA, leading to the production of a potent transcription factor that upregulates UPR target genes.

PERK Pathway

PERK phosphorylates the eukaryotic initiation factor 2 (eIF2α), leading to a reduction in general protein synthesis, which helps to reduce the load of new proteins entering the ER. This pathway also selectively increases the translation of ATF4, a transcription factor that induces genes involved in amino acid metabolism, redox reactions, and apoptosis.

ATF6 Pathway

ATF6 is transported to the Golgi apparatus upon ER stress, where it is cleaved to release a cytosolic fragment that acts as a transcription factor. This fragment moves to the nucleus and activates UPR target genes, including those encoding ER chaperones and components of the ER-associated degradation (ERAD) pathway.

Functions

The primary functions of the UPR are to:

• Enhance the protein folding capacity of the ER by increasing the production of molecular chaperones.
• Decrease the load of new proteins entering the ER by attenuating general protein synthesis.
• Degrade misfolded proteins through the ER-associated degradation (ERAD) pathway.
• Induce apoptosis if the stress cannot be resolved.

Clinical Significance

Dysregulation of the UPR is implicated in various diseases, including neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and Huntington's disease, as well as diabetes, cancer, and inflammatory diseases. Understanding the UPR pathways and their regulation is crucial for developing therapeutic strategies for these conditions.

See Also

• Endoplasmic reticulum stress
• Molecular chaperone
• Protein folding
• ER-associated degradation
• Apoptosis