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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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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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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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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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Endoplasmic Reticulum01:39

Endoplasmic Reticulum

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The Endoplasmic Reticulum (ER) in eukaryotic cells is a substantial network of interconnected membranes with diverse functions, from calcium storage to biomolecule synthesis. A primary component of the endomembrane system, the ER manufactures phospholipids critical for membrane function throughout the cell. Additionally, the two distinct regions of the ER specialize in the manufacture of specific lipids and proteins.
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Related Experiment Video

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Author Spotlight: Exploring the Role of Unfolded Protein Response in HIV-1 Replication and Infectivity
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Endoplasmic Reticulum Membrane Homeostasis and the Unfolded Protein Response.

Robert Ernst1,2, Mike F Renne3,2, Aamna Jain3,2

  • 1Medical Biochemistry and Molecular Biology, Medical Faculty, Saarland University, 66421 Homburg, Germany robert.ernst@uks.eu.

Cold Spring Harbor Perspectives in Biology
|January 22, 2024
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Summary

Aberrant endoplasmic reticulum (ER) membrane compositions, or lipid bilayer stress, activate the unfolded protein response (UPR). This signaling pathway maintains balance between protein and lipid production in the ER.

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • The endoplasmic reticulum (ER) is central to membrane biogenesis, synthesizing most lipids and initiating membrane protein insertion.
  • Maintaining ER membrane composition is crucial for proper protein insertion and folding.
  • The unfolded protein response (UPR) is a key signaling pathway regulating ER homeostasis.

Purpose of the Study:

  • To summarize current knowledge on how ER lipid bilayer stress triggers the UPR.
  • To elucidate the mechanisms linking membrane composition to UPR activation.

Main Methods:

  • Literature review and synthesis of existing research.
  • Analysis of signaling pathways involved in ER stress response.

Main Results:

  • Aberrant ER membrane compositions, termed lipid bilayer stress, are identified as triggers for the UPR.
  • The UPR acts to restore ER homeostasis by balancing protein and lipid synthesis.

Conclusions:

  • Lipid bilayer stress is a significant factor in initiating the UPR.
  • Understanding this interplay is vital for comprehending ER function and cellular stress responses.