Role of Promyelocytic Leukemia (Pml) Sumolation in Nuclear Body Formation, 11s Proteasome Recruitment, and as2O3-Induced Pml or Pml/Retinoic Acid Receptor α Degradation

• DOI: 10.1084/jem.193.12.1361
• Publication Date: 2002-07-26T16:48:33Z
• Authors: Valérie Lallemand...; Jun Zhu; Francine Puvion; Marcel Koken; Nicole Honoré; Alexandre Doubeik...; Estelle Duprez; Pier Paolo Pandolfi; Edmond Puvion; Paul Freemont; Hugues de Thé
• Keywords: Receptors, Retinoic Acid; Retinoic Acid; Amino Acid Motifs; RAR-ALPHA; SP100 PROTEINS; Research & Experimental Medicine; Promyelocytic Leukemia Protein; Arsenicals; Mice; Arsenic Trioxide; Models; Cricetinae; Receptors; Protein Isoforms; 11 Medical and Health Sciences; Cells, Cultured; Adenosine Triphosphatases; 0303 health sciences; Cultured; Research & Experimental; Retinoic Acid Receptor alpha; CREB BINDING-PROTEIN; leukemia; Nuclear Proteins; LOCALIZATION; Oxides; interferon; ONCOGENIC RAS; Neoplasm Proteins; Protein Transport; Medicine, Research & Experimental; nuclear matrix; DAXX; Medicine; Life Sciences & Biomedicine; Proteasome Endopeptidase Complex; PREMATURE SENESCENCE; Cells; Immunology; SUMO-1 Protein; 610; CHO Cells; Models, Biological; Cell Line; 03 medical and health sciences; ubiquitin; Endopeptidases; Animals; Nuclear Matrix; Ubiquitins; Cell Nucleus; Science & Technology; Tumor Suppressor Proteins; arsenic; Biological; SUMO-1 MODIFICATION; Mutation; BODIES; DEPENDENT DEGRADATION; Transcription Factors

Promyelocytic leukemia (PML) is the organizer of nuclear matrix domains, PML nuclear bodies (NBs), with a proposed role in apoptosis control. In acute promyelocytic leukemia, PML/retinoic acid receptor (RAR) α expression disrupts NBs, but therapies such as retinoic acid or arsenic trioxide (As2O3) restore them. PML is conjugated by the ubiquitin-related peptide SUMO-1, a process enhanced by As2O3 and proposed to target PML to the nuclear matrix. We demonstrate that As2O3 triggers the proteasome-dependent degradation of PML and PML/RARα and that this process requires a specific sumolation site in PML, K160. PML sumolation is dispensable for its As2O3-induced matrix targeting and formation of primary nuclear aggregates, but is required for the formation of secondary shell-like NBs. Interestingly, only these mature NBs harbor 11S proteasome components, which are further recruited upon As2O3 exposure. Proteasome recruitment by sumolated PML only likely accounts for the failure of PML-K160R to be degraded. Therefore, studying the basis of As2O3-induced PML/RARα degradation we show that PML sumolation directly or indirectly promotes its catabolism, suggesting that mature NBs could be sites of intranuclear proteolysis and opening new insights into NB alterations found in viral infections or transformation.