Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Haze, K., Yoshida, H., Yanagi, H., Yura, T. The unfolded protein response and cell fate control. The unfolded protein response and endoplasmic reticulum protein targeting machineries converge on the stress sensor IRE1. The IRE1alpha/XBP1s pathway is essential for the glucose response and protection of beta cells. IRE1alpha kinase activation modes control alternate endoribonuclease outputs to determine divergent cell fates. Inositol-requiring enzyme 1 facilitates diabetic wound healing through modulating microRNAs. IRE1alpha cleaves select microRNAs during ER stress to derepress translation of proapoptotic caspase-2. In this study, the process known as regulated IRE1-dependent decay (RIDD) is discovered. Decay of endoplasmic reticulum-localized mRNAs during the unfolded protein response. Regulated Ire1-dependent decay of messenger RNAs in mammalian cells. This article is one of the first reports identifying XBP1 as a downstream target of IRE1α. Complementary signaling pathways regulate the unfolded protein response and are required for C. (2002) identify XBP1 as a downstream target of IRE1α. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. This article is one of the first reports identifying XBP1 as a downstream target of IRE1α.Ĭalfon, M. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Yoshida, H., Matsui, T., Yamamoto, A., Okada, T. The crystal structure of human IRE1 luminal domain reveals a conserved dimerization interface required for activation of the unfolded protein response. This study proposes a direct recognition model for sensing ER stress in yeast. On the mechanism of sensing unfolded protein in the endoplasmic reticulum. Ppp1r15 gene knockout reveals an essential role for translation initiation factor 2 alpha (eIF2alpha) dephosphorylation in mammalian development. Inhibition of a constitutive translation initiation factor 2alpha phosphatase, CReP, promotes survival of stressed cells. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. This study reports the discovery of the consequences of ER stress for protein translation through PERK. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. The zipper model of translational control: a small upstream ORF is the switch that controls structural remodeling of an mRNA leader. Translation reinitiation at alternative open reading frames regulates gene expression in an integrated stress response. Reinitiation involving upstream ORFs regulates ATF4 mRNA translation in mammalian cells. Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast. Signal integration in the endoplasmic reticulum unfolded protein response. Orchestrating the unfolded protein response in health and disease. Adapting proteostasis for disease intervention. In and out of the ER: protein folding, quality control, degradation, and related human diseases.
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