[Unfolded protein response: its role in physiology and physiopathology].
The endoplasmic reticulum (ER) is the first compartment in the secretory pathway. In the ER, proteins fold into their native configuration and are modified by post-translational modifications. Perturbations that alter ER homeostasis therefore disrupt folding and lead to the accumulation of unfolded proteins. These perturbations include modifications of Ca2+ homeostasis, increased demand for protein folding due to elevated synthesis of proteins in specialized cells or expression of a mutant misfolded protein. To limit accumulation of unfolded proteins, the cells have developed a specialized pathway : the unfolded protein response (UPR). UPR involves the activation of three transmembrane proteins of the ER : the PKR-like ER protein kinase (PERK), the activating transcription factor 6 (ATF6) and the inositol requiring enzyme 1 (IRE-1). The activation of all three components of the UPR depends on the dissociation of the luminal chaperone BiP/GRP78 from the luminal part of these proteins. Once activated, these pathways down-regulate protein synthesis through the phosphorylation of eiF2 (eucaryotic translation initiation factor 2) and up-regulate the transcription of genes which encode ER chaperones, protein folding enzymes and components of the ER-associated degradation system (ERAD). Growing evidences indicate that UPR signaling plays critical roles in nutrient sensing, differentiation of secretory cells such as pancreatic b cell and antibody producing plasma cells, glucose homeostasis and in the development of pathologies linked to accumulation of aggregated proteins.
Foufelle
Fabienne
F
Inserm U671, Université Pierre et Marie Curie-Paris 6, UMR S671, Centre biomédical des Cordeliers, France. foufelle@bhdc.jussieu.fr
Ferré
Pascal
P
D051702:Activating Transcription Factor 6 / Q000502:physiology; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism; D003920:Diabetes Mellitus / Q000503:physiopathology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000502:physiology; D006801:Humans; D008322:Mammals / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D018832:Molecular Chaperones / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000503:physiopathology; D011487:Protein Conformation; D011489:Protein Denaturation; D017510:Protein Folding; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D013312:Stress, Physiological / Q000503:physiopathology; D014158:Transcription, Genetic; D019892:eIF-2 Kinase / Q000502:physiology
D051702:Activating Transcription Factor 6; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases; D018832:Molecular Chaperones; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse