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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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Necrosis is considered as an “accidental” or unexpected form of cell death that ends in cell lysis. The first noticeable mention of “necrosis” was in 1859 when Rudolf Virchow used this term to describe advanced tissue breakdown in his compilation titled “Cell Pathology”.
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Translocation of Proteins into the Mitochondria01:19

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Mitochondrial precursors are translocated to the internal subcompartments via independent mechanisms involving distinct protein machineries called translocases.
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Export of Misfolded Proteins out of the ER01:32

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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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Protein Folding Quality Check in the RER01:29

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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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Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
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NFE2L1-mediated proteasome function protects from ferroptosis.

Stefan Kotschi1, Anna Jung1, Nienke Willemsen1

  • 1Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich, Munich, Germany.

Molecular Metabolism
|January 9, 2022
PubMed
Summary
This summary is machine-generated.

Diminished proteasome function is a new feature of ferroptosis. Nuclear factor erythroid-2, like-1 (NFE2L1) protects cells from ferroptosis by maintaining proteasome activity, offering therapeutic potential.

Keywords:
Brown adipose tissueFerroptosisGPX4LipidsProteasomeUbiquitin

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Area of Science:

  • Cell Biology
  • Biochemistry
  • Pathology

Background:

  • Ferroptosis is a regulated cell death pathway implicated in cancer and degenerative diseases.
  • While linked to lipid metabolism, iron homeostasis, and mitochondrial respiration, ferroptosis mechanisms remain incompletely understood.
  • Proteasome function is crucial for cellular protein homeostasis, but its role in ferroptosis is unclear.

Purpose of the Study:

  • To investigate the role of proteasome function in ferroptosis.
  • To identify regulators of proteasome activity during ferroptosis.
  • To explore the therapeutic potential of targeting the NFE2L1-proteasome pathway in ferroptosis-related diseases.

Main Methods:

  • Utilized cellular systems and patient-derived cell lines (SSMD) with mutated GPX4.
  • Investigated the effect of NFE2L1 loss on ferroptosis sensitivity and proteasomal activity.
  • Examined ferroptosis hallmarks in Gpx4-deficient and Nfe2l1-deficient mouse models, including brown adipose tissue (BAT) involution.

Main Results:

  • Diminished proteasome function is identified as a novel mechanistic feature of ferroptosis.
  • Nuclear factor erythroid-2, like-1 (NFE2L1) protects against ferroptosis by sustaining proteasomal activity.
  • Loss of NFE2L1 reduced cell viability during ferroptosis induction and was linked to proteasome regulation.
  • Reduced proteasomal activity and ferroptosis were observed in GPX4-mutated cells and Gpx4-deficient mice.
  • Nfe2l1 deficiency in mice led to BAT involution and ferroptosis hallmarks, including hyperubiquitination of ferroptosis regulators.

Conclusions:

  • The NFE2L1-proteasome pathway is critically involved in ferroptosis.
  • Targeting NFE2L1 activity may enhance ferroptosis-inducing cancer therapies.
  • Modulating NFE2L1 could offer protection against aberrant ferroptosis in neurodegeneration and metabolic disorders.