ER Stress/Unfolded Protein Response

Following translation, secreted and transmembrane proteins enter the lumen of the endoplasmic reticulum (ER), where they are post-translationally modified and properly folded in the presence of specialized chaperone proteins. This process is overwhelmed during ER stress, which can be triggered by stimuli such as nutrient deprivation, infection, toxins or mutations in abundantly expressed proteins.

In severe cases, the accumulation of improperly folded proteins can cause cell death, so in order to relieve ER stress and restore ER homeostasis, the cell activates a series of signaling pathways, collectively called the unfolded protein response (UPR).

The UPR is regulated by three main proteins: inositol-requiring enzyme 1α (IRE1α), PKR-like ER kinase (PERK) and activating transcription factor 6 (ATF6). Under normal conditions these proteins are inhibited via the binding of chaperone protein BIP, also known as GRP78, which is a member of the Hsp70 family. However, under ER stress conditions BIP dissociates to assist with protein folding. This process activates IRE1α and PERK and causes the translocation of ATF6 to the Golgi apparatus, where it is cleaved to initiate UPR-gene transcription.

The UPR results in the reduced synthesis of new proteins, the upregulation of proteins that aid correct protein folding, such as protein disulphide isomerase (PDI), and the upregulation of ER-associated protein degradation program (ERAD) proteins. These linearize improperly folded proteins which are ultimately ubiquitinated and degraded by the proteasome.

In cases of chronic ER stress, homeostasis may not be restored and the cell may initiate cell death. This is seen in a number of neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, which are exacerbated by aggregates of misfolded proteins. The UPR response is also linked to cancer, in which IRE1α mutations are common, as all pathways in the UPR are proposed to promote cancer progression.