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Related Concept Videos

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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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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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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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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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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Related Experiment Video

Updated: Sep 11, 2025

Author Spotlight: Exploring the Role of Unfolded Protein Response in HIV-1 Replication and Infectivity
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Secreted Protein Production is Improved by Controlling Endoplasmic Reticulum Stress Associated Protein Degradation.

Ryan Chauncey Splichal, Christina Chan, S Patrick Walton

    Biorxiv : the Preprint Server for Biology
    |August 13, 2025
    PubMed
    Summary
    This summary is machine-generated.

    Controlling cellular protein degradation pathways, specifically autophagy and proteasome activity, can enhance therapeutic protein production in stressed mammalian cells. This study reveals key insights for optimizing bioprocess yields.

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    Area of Science:

    • Biotechnology
    • Cell Biology
    • Bioprocess Engineering

    Background:

    • Mammalian cells in bioreactors face stress, leading to endoplasmic reticulum (ER) stress and loss of proteostasis.
    • The unfolded protein response (UPR) is activated to manage ER stress, involving autophagy and proteasome pathways.
    • Understanding these pathways is crucial for improving therapeutic protein production.

    Purpose of the Study:

    • To investigate the impact of autophagy and proteasome activity on secreted protein production under ER stress.
    • To identify strategies for enhancing therapeutic protein yield in bioprocesses.

    Main Methods:

    • Used HeLa and MDA-MB-231 cells expressing Gaussia luciferase as a model for therapeutic protein production.
    • Induced ER stress using tunicamycin (TM).
    • Manipulated autophagy and proteasome activity to assess effects on protein secretion.

    Main Results:

    • Tunicamycin exposure reduced protein production and secretion.
    • Inhibiting autophagy improved secretion in stressed cells.
    • Increased proteasomal degradation enhanced secretion, showing a direct correlation between proteasome activity and secretion.

    Conclusions:

    • Protein secretion can be improved by modulating autophagy and proteasome activity.
    • Findings offer strategies for optimizing therapeutic protein production bioprocesses.