title: Arsenic degrades PML or PML-RARalpha through a SUMO-triggered RNF4/ubiquitin-mediated pathway.
abstract: In acute promyelocytic leukaemia (APL), arsenic trioxide induces degradation of the fusion protein encoded by the PML-RARA oncogene, differentiation of leukaemic cells and produces clinical remissions. SUMOylation of its PML moiety was previously implicated, but the nature of the degradation pathway involved and the role of PML-RARalpha catabolism in the response to therapy have both remained elusive. Here, we demonstrate that arsenic-induced PML SUMOylation triggers its Lys 48-linked polyubiquitination and proteasome-dependent degradation. When exposed to arsenic, SUMOylated PML recruits RNF4, the human orthologue of the yeast SUMO-dependent E3 ubiquitin-ligase, as well as ubiquitin and proteasomes onto PML nuclear bodies. Arsenic-induced differentiation is impaired in cells transformed by a non-degradable PML-RARalpha SUMOylation mutant or in APL cells transduced with a dominant-negative RNF4, directly implicating PML-RARalpha catabolism in the therapeutic response. We thus identify PML as the first protein degraded by SUMO-dependent polyubiquitination. As PML SUMOylation recruits not only RNF4, ubiquitin and proteasomes, but also many SUMOylated proteins onto PML nuclear bodies, these domains could physically integrate the SUMOylation, ubiquitination and degradation pathways.
authors.affiliation: Université de Paris 7/CNRS UMR 7151, Equipe Labellisée N11 Ligue Nationale Contre le Cancer, Hôpital St. Louis, 1, Av. C. Vellefaux 75475 Paris CEDEX 10 France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Lallemand-Breitenbach
authors.forename: Marion
authors.initials: M
authors.lastname: Jeanne
authors.forename: Shirine
authors.initials: S
authors.lastname: Benhenda
authors.forename: Rihab
authors.initials: R
authors.lastname: Nasr
authors.forename: Ming
authors.initials: M
authors.lastname: Lei
authors.forename: Laurent
authors.initials: L
authors.lastname: Peres
authors.forename: Jun
authors.initials: J
authors.lastname: Zhou
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Brian
authors.initials: B
authors.lastname: Raught
authors.forename: Hugues
authors.initials: H
authors.lastname: de Thé
mesh_terms: D000818:Animals; D001151:Arsenic / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D006801:Humans; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D025821:Polyubiquitin / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D000071156:Promyelocytic Leukemia Protein; D034741:RNA, Small Interfering; C114070:RNF4 protein, human; D011993:Recombinant Fusion Proteins; D025842:SUMO-1 Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D025821:Polyubiquitin; C070576:PML protein, human; D046988:Proteasome Endopeptidase Complex; D001151:Arsenic