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.

Analyzing the pathways by which retinoic acid (RA) induces promyelocytic leukemia͞retinoic acid receptor ␣ (PML͞RAR␣) catabolism in acute promyelocytic leukemia (APL), we found that, in addition to caspase-mediated PML͞RAR␣ cleavage, RA triggers degradation of both PML͞RAR␣ and RAR␣. Similarly, in non-APL cells, RA directly targeted RAR␣ and RAR␣ fusions to the proteasome degradation pathway. Activation of either RAR␣ or RXR␣ by specific agonists induced degradation of both proteins. Conversely, a mutation in RAR␣ that abolishes heterodimer formation and DNA binding, blocked both RAR␣ and RXR␣ degradation. Mutations in the RAR␣ DNA-binding domain or AF-2 transcriptional activation region also impaired RAR␣ catabolism. Hence, our results link transcriptional activation to receptor catabolism and suggest that transcriptional up-regulation of nuclear receptors by their ligands may be a feedback mechanism allowing sustained target-gene activation.