Role of promyelocytic leukemia (PML) sumolation in nuclear body formation,11S proteasome recruitment, and As2O3-induced PML or PML/retinoic acid receptor alpha degradation

Promyelocytic leukemia (PML) is the organizer of nuclear matrix domains, PM L nuclear bodies (NBs), with a proposed role in apoptosis control. In acute promyelocytic leukemia, PML/retinoic acid receptor (RAR) alpha expression disrupts NBs, but therapies such as retinoic acid or arsenic trioxide (AS(2 )O(3)) restore them. PML is conjugated by the ubiquitin-related peptide SUM O-1, a process enhanced by AS(2)O(3) and proposed to target PML to the nucl ear matrix. We demonstrate that As2O3 triggers the proteasome-dependent deg radation of PML and PML/RAR alpha 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 i s required for the formation of secondary shell-like NBs. Interestingly, on ly these mature NBs harbor 11S proteasome components, which are further rec ruited upon As2O3 exposure. Proteasome recruitment by sumolated PML only li kely accounts for the failure of PML-K160R to be degraded. Therefore, study ing the basis of As2O3-induced PML/RAR alpha degradation we show that PML s umolation directly or indirectly promotes its catabolism, suggesting that m ature NBs could be sites of intranuclear proteolysis and opening new insigh ts into NE alterations found in viral infections or transformation.