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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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Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

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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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Protein Folding Quality Check in the RER01:29

Protein Folding Quality Check in the RER

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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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Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

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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...
4.0K
Protein Modifications in the RER01:26

Protein Modifications in the RER

5.7K
Modification of secretory and transmembrane proteins entering the rough ER begins in the ER lumen. These modifications aid in protein folding and stabilize the acquired tertiary structure. Protein modifications in the rough ER co-occur at different stages of protein folding.
Broadly, these modifications can be categorized into four main categories — glycosylation, formation of disulfide bonds, assembly of protein subunits, and specific proteolytic cleavages like removal of signal...
5.7K
Directing Proteins to the Rough Endoplasmic Reticulum01:34

Directing Proteins to the Rough Endoplasmic Reticulum

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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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Author Spotlight: Exploring the Role of Unfolded Protein Response in HIV-1 Replication and Infectivity
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Reshaping endoplasmic reticulum quality control through the unfolded protein response.

R Luke Wiseman1, Jaleh S Mesgarzadeh1, Linda M Hendershot2

  • 1Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA.

Molecular Cell
|April 22, 2022
PubMed
Summary

Cells adapt endoplasmic reticulum quality control (ERQC) using the unfolded protein response (UPR) during stress. UPR pathways remodel ERQC to maintain protein homeostasis and mitigate diseases linked to misfolding.

Keywords:
ATF6ER-associated degradationERADIRE1PERKXBP1samyloidchaperoneloss-of-function diseaseprotein aggregationprotein misfolding disease

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Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Endoplasmic reticulum quality control (ERQC) pathways maintain protein folding and trafficking fidelity.
  • ERQC is challenged by diverse factors including aging, environmental insults, and tissue-specific demands.
  • Understanding ERQC adaptation is crucial for cellular homeostasis in health and disease.

Purpose of the Study:

  • To elucidate how cells adapt ERQC to meet changing physiological and pathological demands.
  • To highlight the role of the unfolded protein response (UPR) in ERQC adaptation.
  • To explore the therapeutic potential of targeting UPR for protein misfolding diseases.

Main Methods:

  • Review of UPR signaling pathways (IRE1, ATF6, PERK).
  • Analysis of ERQC remodeling mechanisms.
  • Integration of knowledge on UPR's role in maintaining ER function.

Main Results:

  • UPR signaling pathways are activated by ER stress.
  • UPR pathways remodel ERQC to restore ER function and alleviate stress.
  • UPR is essential for maintaining ER function across various tissues.

Conclusions:

  • UPR signaling is a key mechanism for adapting ERQC to cellular demands.
  • Targeting UPR offers a potential therapeutic strategy for protein misfolding diseases.
  • Maintaining ER function via UPR is vital for overall organismal health.