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The p97/VCP segregase is essential for arsenic-induced degradation of PML and PML-RARA

Ellis G Jaffray1, Michael H Tatham1, Barbara Mojsa1

  • 1Centre for Gene Regulation and Expression, School of Life Sciences, University of Dundee , Dundee, UK.

The Journal of Cell Biology
|March 7, 2023
PubMed

Insights

Arsenic therapy for acute promyelocytic leukemia degrades the toxic PML-RARA protein. The p97 enzyme complex is crucial for this degradation process by extracting modified PML proteins from PML bodies.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Oncology

Background:

  • Acute Promyelocytic Leukemia (APL) is driven by the oncogenic Promyelocytic Leukemia (PML)-Retinoic Acid Receptor Alpha (RARA) fusion protein.
  • Arsenic trioxide therapy effectively treats APL by inducing degradation of PML-RARA and PML proteins.
  • SUMOylation and ubiquitination of PML and PML-RARA precede their proteasomal degradation.

Purpose of the Study:

  • To identify novel protein components involved in the arsenic-induced degradation pathway of PML and PML-RARA.
  • To elucidate the role of the p97/VCP segregase complex in the processing of PML bodies.

Main Methods:

  • Proteomics analysis of PML bodies.
  • Pharmacological inhibition and siRNA-mediated depletion of p97/VCP.
  • Immunofluorescence microscopy to visualize PML bodies and protein localization.
  • Western blotting to assess protein modification and degradation.

Main Results:

  • Proteomics identified increased association of p97/VCP segregase with PML bodies upon arsenic treatment.
  • Inhibition of p97 disrupted PML body morphology, increased SUMO- and ubiquitin-modified PML, and blocked arsenic-induced degradation.
  • p97 cofactors UFD1 and NPLOC4 were essential for PML degradation.
  • The UFD1-NPLOC4-p97 complex extracts modified PML from PML bodies for proteasomal degradation.

Conclusions:

  • The UFD1-NPLOC4-p97 segregase complex plays a critical role in arsenic-induced degradation of PML and PML-RARA in APL.
  • This complex facilitates the extraction of ubiquitinated and SUMOylated PML from PML bodies, enabling proteasomal degradation.
  • Targeting the p97 pathway may offer new therapeutic strategies for APL.

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