title: Arkadia, a novel SUMO-targeted ubiquitin ligase involved in PML degradation.
abstract: Arkadia is a RING domain E3 ubiquitin ligase that activates the transforming growth factor β (TGF-β) pathway by inducing degradation of the inhibitor SnoN/Ski. Here we show that Arkadia contains three successive SUMO-interacting motifs (SIMs) that mediate noncovalent interaction with poly-SUMO2. We identify the third SIM (VVDL) of Arkadia to be the most relevant one in this interaction. Furthermore, we provide evidence that Arkadia can function as a SUMO-targeted ubiquitin ligase (STUBL) by ubiquitinating SUMO chains. While the SIMs of Arkadia are not essential for SnoN/Ski degradation in response to TGF-β, we show that they are necessary for the interaction of Arkadia with polysumoylated PML in response to arsenic and its concomitant accumulation into PML nuclear bodies. Moreover, Arkadia depletion leads to accumulation of polysumoylated PML in response to arsenic, highlighting a requirement of Arkadia for arsenic-induced degradation of polysumoylated PML. Interestingly, Arkadia homodimerizes but does not heterodimerize with RNF4, the other STUBL involved in PML degradation, suggesting that these two E3 ligases do not act synergistically but most probably act independently during this process. Altogether, these results identify Arkadia to be a novel STUBL that can trigger degradation of signal-induced polysumoylated proteins.
authors.affiliation: Laboratory of Cell Signaling and Carcinogenesis, INSERM UMR938, Paris, France.
authors.forename: Yigit
authors.initials: Y
authors.lastname: Erker
authors.forename: Helene
authors.initials: H
authors.lastname: Neyret-Kahn
authors.forename: Jacob S
authors.initials: JS
authors.lastname: Seeler
authors.forename: Anne
authors.initials: A
authors.lastname: Dejean
authors.forename: Azeddine
authors.initials: A
authors.lastname: Atfi
authors.forename: Laurence
authors.initials: L
authors.lastname: Levy
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001151:Arsenic / Q000494:pharmacology; D002460:Cell Line / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D000071156:Promyelocytic Leukemia Protein; D021381:Protein Transport / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism; D058207:Sumoylation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D000071156:Promyelocytic Leukemia Protein; D011518:Proto-Oncogene Proteins; C114070:RNF4 protein, human; C060615:SKIL protein, human; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; C070576:PML protein, human; C486067:RNF111 protein, human; D044767:Ubiquitin-Protein Ligases; D001151:Arsenic