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Related Concept Videos

Role of ER in the Secretory Pathway01:17

Role of ER in the Secretory Pathway

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Eukaryotic cells have a special pathway that enables communication between various intracellular membrane-bound compartments and also with the extracellular environment. This pathway is termed as the secretory pathway.
Components of the secretory pathway
About a third of proteins synthesized in the cell are sorted via the secretory route. They shuffle between different compartments in membrane-bound vesicles until they reach their final destination. The main intracellular compartments involved...
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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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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...
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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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Smooth Endoplasmic Reticulum01:21

Smooth Endoplasmic Reticulum

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Smooth endoplasmic reticulum or smooth ER is a sub-organelle with specialized functions in animal cells and plant cells. It is often associated with the tubule morphology of the endoplasmic reticulum.
The ER provides optimal conditions for synthesizing steroid hormones and lipids, such as phospholipids and triglycerides. Traditionally, lipid metabolism was considered to be a smooth ER function. However, there is no direct evidence to prove that rough ER is completely excluded from lipid...
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Curcumin Reduces Pathological Endoplasmic Reticulum Stress through Increasing Proteolysis of Mutant Matrilin-3.

Ella P Dennis1, Robyn N Watson1, Florence McPate1

  • 1International Centre for Life, Biosciences Institute, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.

International Journal of Molecular Sciences
|January 21, 2023
PubMed
Summary

Curcumin, a natural compound, effectively reduces endoplasmic reticulum (ER) stress in a cell model of rare skeletal dysplasia EDM5. This discovery promotes the degradation of mutant matrilin-3, offering a potential new treatment avenue.

Keywords:
chondrodysplasiacurcuminendoplasmic reticulum (ER) stressgenetic skeletal diseasematrilin-3proteasomal degradation

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Area of Science:

  • Biochemistry
  • Cell Biology
  • Genetics

Background:

  • Intracellular retention of mutant cartilage matrix proteins causes endoplasmic reticulum (ER) stress, disrupting ossification in skeletal dysplasias like multiple epiphyseal dysplasia type 5 (EDM5).
  • Targeting ER stress is a promising therapeutic strategy, but no drugs have successfully treated EDM5 caused by mutant matrilin-3 retention.

Purpose of the Study:

  • To identify natural compounds that can reduce pathological ER stress in a cell model of EDM5.
  • To investigate the mechanism by which potential treatments alleviate ER stress.

Main Methods:

  • Utilized a luciferase ER stress screening assay to identify effective compounds.
  • Tested the efficacy of curcumin in a cell model of EDM5.
  • Investigated the effect of curcumin on mutant matrilin-3 degradation via the proteasome.

Main Results:

  • Curcumin was identified as a natural chemical capable of reducing pathological ER stress in the EDM5 cell model.
  • Curcumin promotes the proteasomal degradation of mutant matrilin-3.
  • This study represents the first demonstration of a natural chemical's success in reducing ER stress in EDM5.

Conclusions:

  • Curcumin shows potential as an in vitro treatment for EDM5 by alleviating ER stress.
  • Further research into novel delivery strategies for curcumin is warranted to enhance bioavailability and clinical impact.
  • This finding offers hope for treating this rare skeletal disease and potentially other conditions involving ER stress.