ER stress activates a signaling network called the Unfolded Protein Response (UPR) to alleviate this stress and restore ER homeostasis, promoting cell survival and adaptation. However, under unresolvable ER stress conditions, UPR promotes apoptosis. UPR is initiated by three ER transmembrane proteins: Inositol Requiring 1 (IRE1), PKR-like ER kinase (PERK), and Activating Transcription Factor 6 (ATF6). During unstressed conditions, the ER chaperone, immunoglobin binding protein (BiP), binds to the luminal domains of these master regulators, keeping them inactive. Upon ER stress, BiP dissociates from these sensors resulting in their activation.IRE1, a type I ER transmembrane kinase, senses ER stress by its N-terminal luminal domain. Upon sensing the presence of unfolded or misfolded proteins, IRE1 dimerizes and autophosphorylates to become active. Activated IRE1 splices X-box binding protein 1 (XBP1) mRNA . Spliced XBP1 mRNA encodes a basic leucine zipper (b-ZIP) transcription factor that upregulates UPR target genes, including genes that function in ERAD (endoplasmic-reticulum-associated protein degradation) such as ER-degradation-enhancing-α-mannidose-like protein (EDEM) , as well as genes that function in folding proteins such as protein disulfide isomerase (PDI).
PERK is also a type I ER transmembrane kinase. Similar to IRE1, when activated by ER stress, PERK oligomerizes, autophosphorylates, and then directly phosphorylates eukaryotic initiation factor 2 alpha (eIF2α) on Ser51. Phosphorylated eIF2α prevents formation of ribosomal initiation complexes leading to global mRNA translational attenuation. This reduction in ER workload protects cells from ER stress-mediated apoptosis. Meanwhile, some mRNAs require eIF2α phosphorylation for translation, such as the mRNA encoding activating transcription factor 4 (ATF4). ATF4 is a b-ZIP transcription factor that regulates several UPR target genes including those involved in ER stress-mediated apoptosis such as C/EBP homologous protein (CHOP).
A third regulator of ER stress signaling is the type II ER transmembrane transcription factor, ATF6. Upon ER stress conditions, ATF6 transits to the Golgi where it is cleaved by proteases, generating an activated b-ZIP factor. This processed form of ATF6 translocates to the nucleus to activate UPR genes involved in protein folding, processing, and degradation.
The UPR adaptive response includes upregulation of molecular chaperones and protein processing enzymes to increase folding and handling efficiency, translational attenuation to reduce ER workload and prevent further accumulation of unfolded proteins, and an increase in (ERAD) and autophagy components to promote clearance of unwanted proteins.
The UPR removes harmful proteins by regulating expression of ERAD genes. During ERAD, misfolded and unfolded proteins are recognized by ER chaperones, retro-translocated out of the ER into the cytosol, and finally ubiquitinated and degraded by the proteasome. (Upgraded 9/2019)