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Assays for the Degradation of Misfolded Proteins in Cells
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Assays for the Degradation of Misfolded Proteins in Cells

Published on: August 28, 2016

Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway

Valérie Lallemand-Breitenbach1, Marion Jeanne, Shirine Benhenda

  • 1Université de Paris 7/CNRS UMR 7151, Equipe Labellisée N11 Ligue Nationale Contre le Cancer, Hôpital St. Louis, 1, Av. C. Vellefaux 75475 Paris CEDEX 10 France.

Nature Cell Biology
|April 15, 2008
PubMed

Insights

Arsenic trioxide triggers PML degradation in acute promyelocytic leukaemia (APL) by initiating SUMOylation-dependent polyubiquitination. This PML-RARA oncogene catabolism is crucial for arsenic

Area of Science:

  • Molecular Biology
  • Oncology
  • Cell Biology

Background:

  • Arsenic trioxide is a key treatment for acute promyelocytic leukaemia (APL), inducing leukaemic cell differentiation and remission.
  • The mechanism involves degradation of the PML-RARA oncogene, but the specific degradation pathway and role of catabolism remain unclear.
  • SUMOylation of the PML moiety was previously suggested but not fully elucidated.

Purpose of the Study:

  • To elucidate the degradation pathway of the PML-RARA fusion protein induced by arsenic trioxide in APL.
  • To investigate the role of PML-RARalpha catabolism in the therapeutic response to arsenic trioxide.
  • To identify the specific E3 ubiquitin ligase involved in arsenic-induced PML degradation.

Main Methods:

  • Demonstration of arsenic-induced PML SUMOylation triggering Lys 48-linked polyubiquitination and proteasome degradation.
  • Recruitment analysis of RNF4, ubiquitin, and proteasomes to PML nuclear bodies upon arsenic exposure.
  • Assessment of arsenic-induced differentiation using non-degradable PML-RARalpha SUMOylation mutants and dominant-negative RNF4 in APL cells.

Main Results:

  • Arsenic-induced PML SUMOylation directly leads to its polyubiquitination and proteasomal degradation.
  • RNF4, a SUMO-dependent E3 ubiquitin ligase, is recruited to PML nuclear bodies along with ubiquitin and proteasomes.
  • Impaired arsenic-induced differentiation in cells with non-degradable PML-RARalpha or dominant-negative RNF4 confirms the critical role of catabolism.

Conclusions:

  • PML is identified as the first protein degraded via SUMO-dependent polyubiquitination, mediated by RNF4.
  • PML-RARalpha catabolism is essential for the therapeutic efficacy of arsenic trioxide in APL.
  • PML nuclear bodies may serve as platforms integrating SUMOylation, ubiquitination, and degradation pathways.

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