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The p97-UBXD8 complex maintains peroxisome abundance by suppressing pexophagy

Iris D Montes1, Suganthan Amirthagunanathan2, Amit S Joshi2

  • 1Department of Developmental Molecular and Chemical Biology, Tufts University School of Medicine, Boston MA.

Biorxiv : the Preprint Server for Biology
|October 10, 2024
PubMed

Insights

The p97-UBXD8 complex is crucial for maintaining peroxisome abundance by preventing their degradation through selective autophagy (pexophagy). Loss of this complex increases peroxisome turnover, impacting cellular metabolism.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Organelle Biology

Background:

  • Peroxisomes are essential eukaryotic organelles involved in metabolism.
  • Peroxisome biogenesis disorders highlight their importance and link to metabolic disruption.
  • Selective autophagy (pexophagy) regulates peroxisome abundance via ubiquitylation, but mechanisms are unclear.

Purpose of the Study:

  • To investigate the role of the AAA-ATPase p97 and its adaptor UBXD8 in peroxisome homeostasis.
  • To elucidate the mechanisms governing pexophagy in mammalian cells.

Main Methods:

  • Quantitative proteomics to identify proteins affected by UBXD8 loss.
  • Cellular assays to assess peroxisome abundance and turnover.
  • Genetic manipulation (depletion, overexpression) of key proteins involved in autophagy and ubiquitylation.

Main Results:

  • Loss of UBXD8 or p97 leads to a decrease in peroxisomes, independent of ER-associated degradation.
  • Peroxisomal turnover via autophagy increases upon UBXD8 or p97 depletion.
  • Overexpression of USP30 or depletion of autophagy proteins rescues peroxisome loss.
  • Ubiquitylation of PMP70 increases in UBXD8 or p97 deficient cells.

Conclusions:

  • The p97-UBXD8 complex suppresses pexophagy, thereby maintaining peroxisome abundance.
  • This pathway represents a novel regulatory mechanism for peroxisome homeostasis.
  • Disruption of this complex impacts lipid metabolism and cellular function.

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