Abstract
The unfolded protein response (UPR) occurs in response to endoplasmic reticulum (ER) stress caused by the accumulation of unfolded or misfolded proteins in the ER. The UPR is comprised of three signaling pathways that promote cytoprotective functions to correct ER stress; however, if ER stress cannot be resolved the UPR results in apoptosis of affected cells. The UPR is an important feature of various human diseases, including multiple sclerosis (MS). Recent studies have shown several components of the UPR are upregulated in the multiple cell types in MS lesions, including oligodendrocytes, T cells, microglia/macrophages, and astrocytes. Data from animal model studies, particularly studies of experimental autoimmune encephalomyelitis (EAE) and the cuprizone model, imply an important role of the UPR activation in oligodendrocytes in the development of MS. In this review we will cover current literature on the UPR and the evidence for its role in the development of MS.
Highlights
Three ER-transmembrane proteins have been identified as the transducers of the unfolded protein response (UPR), pancreatic endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6)
IRE1 is activated by homodimerization and autophosphorylation in conditions of ER stress. p-IRE1 splices X-box binding protein 1 (XBP1) mRNA to produce the spliced XBP1 (sXBP1), which induces cytoprotective genes and ER expansion
ER stress results in the translocation of ATF6 to the Golgi complex where it is activated by proteolytic cleavage by the proteases S1P and S2P resulting in the 50 kDa cleaved ATF6 fragment, which stimulates the expression of chaperones
Summary
Reviewed by: Monique Stins, Johns Hopkins University, USA Christian Gonzalez-Billault, Universidad de Chile, Chile. The unfolded protein response (UPR) occurs in response to endoplasmic reticulum (ER) stress caused by the accumulation of unfolded or misfolded proteins in the ER. The UPR is an important feature of various human diseases, including multiple sclerosis (MS). Recent studies have shown several components of the UPR are upregulated in the multiple cell types in MS lesions, including oligodendrocytes, T cells, microglia/macrophages, and astrocytes. Data from animal model studies, studies of experimental autoimmune encephalomyelitis (EAE) and the cuprizone model, imply an important role of the UPR activation in oligodendrocytes in the development of MS.
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