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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

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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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The Proteasome01:13

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Eukaryotic cells can degrade proteins through several pathways. One of the most important among these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
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The Proteasome02:18

The Proteasome

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Eukaryotic cells can degrade proteins through several pathways. One of the most important amongst these is the ubiquitin-proteasome pathway. It helps the cell eliminate the misfolded, damaged, or unwarranted cytoplasmic proteins in a highly specific manner.
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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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Targeting the unfolded protein response for disease intervention.

Alexis Rivas1, René Luis Vidal, Claudio Hetz

  • 1University of Chile, Biomedical Neuroscience Institute, Faculty of Medicine , Santiago , Chile.

Expert Opinion on Therapeutic Targets
|July 14, 2015
PubMed
Summary

The unfolded protein response (UPR) pathway is implicated in diseases like diabetes, neurodegeneration, and cancer. Targeting UPR signaling shows therapeutic potential, but combinatorial approaches with natural compounds may mitigate side effects.

Keywords:
endoplasmic reticulum stress signaling.pharmacological modulatorprotein misfolding disordersunfolded protein response

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Area of Science:

  • Cellular Biology
  • Molecular Medicine
  • Pathophysiology

Background:

  • Misfolded protein accumulation in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR).
  • The UPR is a cellular adaptive mechanism to restore ER proteostasis, but chronic stress leads to apoptosis.
  • ER stress and UPR activation are increasingly linked to various human diseases.

Purpose of the Study:

  • To review the role of the UPR in driving pathologies such as diabetes, neurodegenerative diseases, and cancer.
  • To highlight the involvement of specific UPR signaling components in different diseases using preclinical and genetic models.

Main Methods:

  • Literature review focusing on the UPR.
  • Analysis of preclinical models investigating UPR signaling.
  • Examination of pharmacological and genetic manipulation of UPR pathways.

Main Results:

  • The UPR is a key player in the pathogenesis of diabetes, neurodegeneration, and cancer.
  • Specific UPR signaling components are differentially involved in various disease contexts.
  • Small molecules targeting UPR components show promise in disease models.

Conclusions:

  • Modulating UPR signaling offers therapeutic potential for stress-related diseases.
  • Combinatorial therapies using drugs and natural compounds may overcome side effects associated with chronic UPR modulation.
  • Targeting ER proteostasis networks presents a novel therapeutic strategy.