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Related Concept Videos

The Unfolded Protein Response01:37

The Unfolded Protein Response

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The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
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Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
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The organelle-specific signaling sequences direct proteins synthesized in the cytosol to their final destination like ER, mitochondria, peroxisomes, etc. Some of the proteins directed to ER are then trafficked via vesicles to other organelles within the cell or the extracellular environment through the Golgi complex. For example, the rough ER synthesizes soluble proteins for transportation to the lysosomes or secretion out of the cell. It can also synthesize transmembrane proteins that can...
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ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
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Cotranslational Protein Translocation01:20

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Translocation of proteins across membranes is an ancient process that occurs even in bacteria and archaebacteria. In fact, the components of the translocation machinery are still conserved between prokaryotes and eukaryotes.
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Export of Misfolded Proteins out of the ER01:32

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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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The Unfolded Protein Response: An Overview.

Adam Read1,2, Martin Schröder1,2

  • 1Department of Biosciences, Durham University, South Road, Durham DH1 3LE, UK.

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The unfolded protein response (UPR) maintains endoplasmic reticulum homeostasis by activating three key pathways: IRE1, PERK, and ATF6. If the UPR fails, sustained signaling can trigger programmed cell death.

Keywords:
ATF6ERADIRE1PERKRIDDUPRinactivation

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The unfolded protein response (UPR) is a cellular mechanism crucial for maintaining endoplasmic reticulum (ER) protein homeostasis.
  • UPR activation is triggered by cellular stresses like hypoxia or altered glycosylation, leading to an accumulation of unfolded proteins within the ER.
  • The UPR involves three primary signaling pathways: IRE1, PERK, and ATF6, each playing a critical role in restoring ER protein balance.

Purpose of the Study:

  • To elucidate the mechanisms and significance of the unfolded protein response (UPR) in cellular protein homeostasis.
  • To detail the roles of the three main UPR signaling pathways (IRE1, PERK, ATF6) in managing endoplasmic reticulum stress.
  • To explore the consequences of UPR failure, including the potential for programmed cell death.

Main Methods:

  • The study focuses on the signaling cascades of the UPR, particularly the IRE1 pathway, which is conserved in yeast and mammals.
  • Analysis involves understanding the spliceosome-independent splicing of HAC1 in yeast and XBP1 in mammalian cells.
  • Examination of PERK's role in regulating protein synthesis and ATF6's function in nuclear gene expression modulation.

Main Results:

  • The IRE1 pathway, the most studied, involves the splicing of HAC1 or XBP1, crucial for UPR activation.
  • PERK pathway activation leads to a reduction in protein synthesis, alleviating the folding load on the ER.
  • The ATF6 pathway results in the nuclear transport of a cleaved fragment, altering gene expression to aid in protein folding and ER function.

Conclusions:

  • The UPR, through IRE1, PERK, and ATF6 pathways, is essential for cellular adaptation to ER stress and maintaining protein homeostasis.
  • Sustained activation of UPR signaling, indicating a failure to resolve ER stress, can ultimately lead to programmed cell death.
  • Understanding the UPR pathways provides insights into cellular responses to stress and potential therapeutic targets for diseases associated with ER dysfunction.