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

Ellis G. Jaffray, Michael H. Tatham, Barbara Mojsa, Magda Liczmanska, Alejandro Rojas-Fernandez, Yili Yin, Graeme Ball, Ronald T. Hay (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
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Abstract

Acute Promyelocytic Leukemia is caused by expression of the oncogenic Promyelocytic Leukemia (PML)–Retinoic Acid Receptor Alpha (RARA) fusion protein. Therapy with arsenic trioxide results in degradation of PML-RARA and PML and cures the disease. Modification of PML and PML-RARA with SUMO and ubiquitin precedes ubiquitin-mediated proteolysis. To identify additional components of this pathway, we performed proteomics on PML bodies. This revealed that association of p97/VCP segregase with PML bodies is increased after arsenic treatment. Pharmacological inhibition of p97 altered the number, morphology, and size of PML bodies, accumulated SUMO and ubiquitin modified PML and blocked arsenic-induced degradation of PML-RARA and PML. p97 localized to PML bodies in response to arsenic, and siRNA-mediated depletion showed that p97 cofactors UFD1 and NPLOC4 were critical for PML degradation. Thus, the UFD1-NPLOC4-p97 segregase complex is required to extract poly-ubiquitinated, poly-SUMOylated PML from PML bodies, prior to degradation by the proteasome.
Original languageEnglish
Article numbere202201027
Number of pages19
JournalJournal of Cell Biology
Volume222
Issue number4
DOIs
Publication statusPublished - 28 Feb 2023

Keywords

  • Cancer
  • Protein homeostasis

ASJC Scopus subject areas

  • Cell Biology

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