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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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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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Intralumenal Vesicles and Multivesicular Bodies01:38

Intralumenal Vesicles and Multivesicular Bodies

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Intraluminal vesicles (ILVs) are small vesicles 50-80 nm in diameter formed during the maturation of early endosomes. A specialized endosome containing numerous ILVs is called a multivesicular body (MVB). ILVs contain internalized molecules such as antigens, nucleic acids, proteins, and metabolites. Some of these molecules are released from the MVBs inside exosomes and are transported to other cells. Other MVBs contain molecules that are retained in the ILVs and are later degraded within the...
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Directing Proteins to the Rough Endoplasmic Reticulum01:34

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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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Vesicular Tubular Clusters01:45

Vesicular Tubular Clusters

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After budding out from the ER membrane, some COPII vesicles lose their coat and fuse with one another to form larger vesicles and interconnected tubules called vesicular tubular clusters or VTCs. These clusters constitute a compartment at the ER-Golgi interface known as ERGIC (Endoplasmic Reticulum Golgi Intermediate Compartment). The ERGIC is a mobile membrane-bound cargo transport system that sorts proteins secreted from ER and delivers them to the Golgi.
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Related Experiment Video

Updated: Nov 2, 2025

Visualization and Quantification of Endogenous Intra-Organelle Protein Interactions at ER-Mitochondria Contact Sites by Proximity Ligation Assays
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VPS13D interacts with VCP/p97 and negatively regulates endoplasmic reticulum-mitochondria interactions.

Yuanjiao Du1, Jingru Wang1, Juan Xiong2

  • 1Department of Biochemistry and Molecular Biology, School of Basic Medicine.

Molecular Biology of the Cell
|June 16, 2021
PubMed
Summary

Vacuolar protein sorting-associated protein 13D (VPS13D) negatively regulates membrane contact sites between the endoplasmic reticulum and mitochondria. Loss of VPS13D causes excessive tethering, impacting mitochondrial function and linked to neurodegenerative diseases.

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Area of Science:

  • Cell Biology
  • Molecular Biology
  • Neuroscience

Background:

  • Membrane contact sites (MCSs) between the endoplasmic reticulum (ER) and mitochondria are crucial for cellular processes.
  • Dysregulation of ER-mitochondria MCSs is implicated in neurodegenerative diseases.
  • Mechanisms controlling ER-mitochondria interactions remain largely unknown.

Purpose of the Study:

  • To investigate the role of vacuolar protein sorting-associated protein 13D (VPS13D) in regulating ER-mitochondria MCSs.
  • To elucidate the molecular mechanisms underlying VPS13D's function at these contacts.

Main Methods:

  • CRISPR-based screening to identify regulators of ER-mitochondria contacts.
  • Yeast-two-hybrid assays to identify interacting proteins.
  • Confocal microscopy to assess mitochondrial morphology and distribution.
  • Western blotting to evaluate protein levels and interactions.

Main Results:

  • VPS13D negatively regulates ER-mitochondria MCSs, with VPS13D suppression leading to excessive tethering.
  • VPS13D interacts with valosin-containing protein (VCP/p97) and influences VAPB levels at ER-mitochondria contacts.
  • VPS13D is essential for the stability of VCP/p97.
  • Loss of VPS13D causes severe defects in mitochondrial morphology, distribution, and DNA synthesis.

Conclusions:

  • VPS13D acts as a negative regulator of ER-mitochondria MCSs, partly via its interaction with VCP/p97.
  • VPS13D's function is critical for maintaining mitochondrial homeostasis.
  • Understanding VPS13D's role provides insights into potential therapeutic targets for neurodegenerative diseases associated with MCS dysfunction.