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, PML 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 (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/RARalpha 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/RARalpha 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.
Lallemand-Breitenbach
V
V
Centre National de la Recherche Scientifique (CNRS) UPR 9051, Laboratoire Associé N degrees 11 du Comité de Paris de la Ligue Nationale Contre le Cancer, Université Paris VII, Hôpital St. Louis 1, 75475 Paris Cedex 10, France.
Zhu
J
J
Puvion
F
F
Koken
M
M
Honoré
N
N
Doubeikovsky
A
A
Duprez
E
E
Pandolfi
P P
PP
Puvion
E
E
Freemont
P
P
de Thé
H
H
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D020816:Amino Acid Motifs; D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D016466:CHO Cells; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D006224:Cricetinae; D010450:Endopeptidases; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015530:Nuclear Matrix / Q000378:metabolism*; D009687:Nuclear Proteins; D010087:Oxides / Q000494:pharmacology*; D000071156:Promyelocytic Leukemia Protein; D046988:Proteasome Endopeptidase Complex; D020033:Protein Isoforms / Q000737:chemistry; D021381:Protein Transport; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D025842:SUMO-1 Protein; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins / Q000378:metabolism*
D001152:Arsenicals; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D010087:Oxides; C513293:Pml protein, mouse; D000071156:Promyelocytic Leukemia Protein; D020033:Protein Isoforms; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D025842:SUMO-1 Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; D010450:Endopeptidases; D046988:Proteasome Endopeptidase Complex; C119011:26S proteasome non-ATPase regulatory subunit 13; D000251:Adenosine Triphosphatases; D000077237:Arsenic Trioxide