Reactome | Unfolded Protein Response (UPR)

Unfolded Protein Response (UPR)

Stable Identifier

R-HSA-381119

Type

Pathway

Species

Homo sapiens

Compartment

Golgi membrane, cytosol, endoplasmic reticulum lumen, endoplasmic reticulum membrane, nucleoplasm

ReviewStatus

5/5

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The Unfolded Protein Response (UPR) is a regulatory system that protects the Endoplasmic Reticulum (ER) from overload. The UPR is provoked by the accumulation of improperly folded protein in the ER during times of unusually high secretion activity. Analysis of mutants with altered UPR, however, shows that the UPR is also required for normal development and function of secretory cells.
One level at which the URP operates is transcriptional and translational regulation: mobilization of ATF6, ATF6B, CREB3 factors and IRE1 leads to increased transcription of genes encoding chaperones, while mobilization of PERK (pancreatic eIF2alpha kinase, EIF2AK3) leads to phosphorylation of the translation initiation factor eIF2alpha and global down-regulation of protein synthesis.
ATF6, ATF6B, and CREB3 factors (CREB3 (LUMAN), CREB3L1 (OASIS), CREB3L2 (BBF2H7, Tisp40), CREB3L3 (CREB-H), and CREB3L4 (CREB4)) are membrane-bound transcription activators that respond to ER stress by transiting from the ER membrane to the Golgi membrane where their transmembrane domains are cleaved, releasing their cytosolic domains to transit to the nucleus and activate transcription of target genes. IRE1, also a resident of the ER membrane, dimerizes and autophosphorylates in response to ER stress. The activated IRE1 then catalyzes unconventional splicing of XBP1 mRNA to yield an XBP1 isoform that is targeted to the nucleus and activates chaperone genes.

Literature References

PubMed ID	Title	Journal	Year
18436705	The unfolded protein response: a pathway that links insulin demand with beta-cell failure and diabetes Kaufman, RJ, Scheuner, D	Endocr Rev	2008
16365312	On the mechanism of sensing unfolded protein in the endoplasmic reticulum Walter, P, Finer-Moore, JS, Papa, FR, Stroud, RM, Credle, JJ	Proc Natl Acad Sci U S A	2005
27067637	Endoplasmic reticulum stress and the unfolded protein response in pancreatic islet inflammation Allagnat, F, Meyerovich, K, Cardozo, AK, Ortis, F	J. Mol. Endocrinol.	2016
18038217	Endoplasmic reticulum stress responses Schröder, M	Cell Mol Life Sci	2008
15952902	The mammalian unfolded protein response Schröder, M, Kaufman, RJ	Annu Rev Biochem	2005
18048764	The role for endoplasmic reticulum stress in diabetes mellitus Cardozo, AK, Eizirik, DL, Cnop, M	Endocr Rev	2008