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Purification of Ubiquitinated p53 Proteins from Mammalian Cells
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Purification of Ubiquitinated p53 Proteins from Mammalian Cells

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Regulation of protein quality control by UBE4B and LSD1 through p53-mediated transcription

Goran Periz1, Jiayin Lu1, Tao Zhang1

  • 1Department of Biochemistry and Molecular Biology and Department of Neuroscience, Bloomberg School of Public Health and School of Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.

Plos Biology
|April 4, 2015
PubMed

Insights

Inactivating genes ufd-2 and spr-5 suppresses neurotoxicity from misfolded proteins. Their human counterparts, UBE4B and LSD1, enhance protein clearance, revealing a new quality control pathway involving transcription factor p53.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Neuroscience

Background:

  • Protein quality control (PQC) is vital for cellular health, preventing the accumulation of misfolded and aggregated proteins.
  • Dysfunctional PQC is implicated in various neurodegenerative diseases, highlighting the need for therapeutic targets.
  • Identifying novel pathways that enhance PQC is crucial for combating proteotoxicity.

Purpose of the Study:

  • To identify genetic factors that suppress neurotoxicity caused by misfolded proteins.
  • To elucidate the molecular mechanisms underlying protein clearance and PQC.
  • To explore the therapeutic potential of augmenting PQC pathways.

Main Methods:

  • Utilized Caenorhabditis elegans as a model organism to screen for suppressors of neurotoxicity.
  • Investigated the function of mammalian orthologs, UBE4B and LSD1, in protein degradation.
  • Employed unbiased screening to identify downstream effectors in the PQC pathway.

Main Results:

  • Loss of function in ufd-2 and spr-5 genes synergistically suppressed neurotoxicity in C. elegans.
  • Human orthologs UBE4B (ubiquitin ligase) and LSD1 (lysine-specific demethylase) promote clearance of misfolded proteins in mammalian cells.
  • Activation of both proteasomal and autophagic degradation pathways was observed.
  • Transcription factor p53 was identified as a key downstream effector and shared substrate of UBE4B and LSD1.

Conclusions:

  • A novel PQC pathway regulated by UBE4B, LSD1, and p53 has been identified.
  • Augmenting this pathway represents a promising, broad-spectrum strategy against proteotoxicity and neurodegeneration.
  • Targeting transcription factor regulation offers a new avenue for therapeutic intervention in protein misfolding diseases.

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