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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

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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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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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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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Related Experiment Video

Updated: May 28, 2025

Evaluation of LC3-II Release via Extracellular Vesicles in Relation to the Accumulation of Intracellular LC3-positive Vesicles
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Enhanced secretion of the amyotrophic lateral sclerosis ALS-associated misfolded TDP-43 mediated by the ER-ubiquitin

Flavien Picard1, Takashi Nonaka2, Edwige Belotti1

  • 1Institut NeuroMyoGène-PGNM, Faculté de Médecine Rockefeller, Université Claude Bernard Lyon, Lyon, France.

Cellular and Molecular Life Sciences : CMLS
|February 13, 2025
PubMed
Summary

The study reveals that USP19 protein promotes the secretion of misfolded TDP-43, a key factor in amyotrophic lateral sclerosis (ALS). This discovery offers potential new therapeutic targets for ALS and related proteinopathies.

Keywords:
ALSAggregatesAutophagosomesAutophagyEndosomesMisfoldingRelease/secretionTDP-43USP19Ubiquitin peptidase

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Area of Science:

  • Cell Biology
  • Neuroscience
  • Molecular Biology

Background:

  • Proteinopathies like ALS involve misfolded protein accumulation.
  • Cellular quality control systems often fail to clear these aberrant proteins.
  • Misfolded TDP-43 aggregates are a hallmark of ALS pathology.

Purpose of the Study:

  • To investigate the role of Endoplasmic Reticulum-associated ubiquitin peptidase USP19 in the secretion of misfolded TDP-43.
  • To elucidate the cellular and molecular mechanisms underlying USP19-mediated secretion of misfolded proteins.

Main Methods:

  • Overexpression of USP19 in cellular models.
  • Analysis of protein secretion using soluble and aggregated TDP-43.
  • Investigation of cellular compartments (autophagosomes, endosomes, lysosomes).
  • Utilizing dominant-negative mutants and small interfering RNAs (siRNAs).

Main Results:

  • USP19 overexpression significantly enhances the secretion of both soluble and aggregated misfolded TDP-43.
  • USP19's ER anchoring and ubiquitin peptidase activity are essential for this secretion.
  • The process involves early autophagosomal and late endosomal/amphisomal compartments, but not lysosomes.
  • Key cellular trafficking factors (ATG7, ESCRT-O, Rab GTPases, VAMP7) and cochaperone DNAJC5/CSPα modulate USP19-mediated secretion.

Conclusions:

  • USP19 plays a critical role in the novel misfolding-associated protein secretion (MAPS) pathway for TDP-43.
  • This mechanism highlights cellular strategies for managing misfolded protein export.
  • Findings suggest potential therapeutic avenues for ALS and other proteinopathies targeting USP19.