Endoplasmic Reticulum Stress Sensing in the Unfolded Protein Response
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TLDR
The mechanistic principles of ER stress sensing are the focus of this review, and yeast Ire1 directly binds to unfolded proteins, which induces its oligomerization and activation.Abstract:
Secretory and transmembrane proteins enter the endoplasmic reticulum (ER) as unfolded proteins and exit as either folded proteins in transit to their target organelles or as misfolded proteins targeted for degradation. The unfolded protein response (UPR) maintains the protein-folding homeostasis within the ER, ensuring that the protein-folding capacity of the ER meets the load of client proteins. Activation of the UPR depends on three ER stress sensor proteins, Ire1, PERK, and ATF6. Although the consequences of activation are well understood, how these sensors detect ER stress remains unclear. Recent evidence suggests that yeast Ire1 directly binds to unfolded proteins, which induces its oligomerization and activation. BiP dissociation from Ire1 regulates this oligomeric equilibrium, ultimately modulating Ire1’s sensitivity and duration of activation. The mechanistic principles of ER stress sensing are the focus of this review.read more
Citations
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Journal ArticleDOI
Clustering of IRE1α depends on sensing ER stress but not on its RNase activity
Daniela Ricci,Ilaria Marrocco,Daniel M. Blumenthal,Miriam Dibos,Daniela Eletto,Jade Vargas,Sarah Boyle,Yuichiro Iwamoto,Steven Chomistek,James C. Paton,Adrienne W. Paton,Yair Argon +11 more
TL;DR: The sensors of the unfolded protein response react to endoplasmic reticulum (ER) stress by transient activation of their enzymatic activities, which initiate various signaling cascades, and data suggest that IRE1α clustering can follow distinct pathways upon activation of the sensor.
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TL;DR: The knockdown of PERK attenuated NaAsO2-induced autophagy in INS-1 cells, which indicated that arsenic impaired β cell function through ER stress-autophagy pathway, and provided new mechanistic insights into arsenic-related diabetes.
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Protein kinase R(PKR)–like endoplasmic reticulum kinase (PERK) inhibitors: a patent review (2010-2015)
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References
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Journal ArticleDOI
Oligomerization and phosphorylation of the Ire1p kinase during intracellular signaling from the endoplasmic reticulum to the nucleus.
Caroline E. Shamu,Peter Walter +1 more
TL;DR: Molecular genetic and biochemical studies described here suggest that, as in the case of growth factor receptors of higher eukaryotic cells, Ire1p oligomerizes in response to the accumulation of unfolded proteins in the ER and is phosphorylated in trans by otherIre1p molecules as a result of oligomerization.
Journal ArticleDOI
The Unfolded Protein Response: From Stress Pathway to Homeostatic Regulation
Peter Walter,David Ron +1 more
TL;DR: The vast majority of proteins that a cell secretes or displays on its surface first enter the endoplasmic reticulum, where they fold and assemble, and only properly assembled proteins advance from the ER to the cell surface.
Journal ArticleDOI
XBP1 mRNA Is Induced by ATF6 and Spliced by IRE1 in Response to ER Stress to Produce a Highly Active Transcription Factor
TL;DR: The transcription factor XBP1, a target of ATF6, is identified as a mammalian substrate of such an unconventional mRNA splicing system and it is shown that only the spliced form of X BP1 can activate the UPR efficiently.
Journal ArticleDOI
Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase
TL;DR: The cloning of perk is described, a gene encoding a type I transmembrane ER-resident protein that contains a protein-kinase domain most similar to that of the known eIF2α kinases, PKR and HRI that implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.
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