title: CRL3IBTK Regulates the Tumor Suppressor Pdcd4 through Ubiquitylation Coupled to Proteasomal Degradation.
abstract: The human inhibitor of Bruton's tyrosine kinase isoform α (IBtkα) is a BTB protein encoded by the IBTK gene, which maps to chromosomal locus 6q14.1, a mutational hot spot in lymphoproliferative disorders. Here, we demonstrate that IBtkα forms a CRL3(IBTK) complex promoting its self-ubiquitylation. We identified the tumor suppressor Pdcd4 as IBtkα interactor and ubiquitylation substrate of CRL3(IBTK) for proteasomal degradation. Serum-induced degradation of Pdcd4 required both IBtkα and Cul3, indicating that CRL3(IBTK) regulated the Pdcd4 stability in serum signaling. By promoting Pdcd4 degradation, IBtkα counteracted the suppressive effect of Pdcd4 on translation of reporter luciferase mRNAs with stem-loop structured or unstructured 5'-UTR. IBtkα depletion by RNAi caused Pdcd4 accumulation and decreased the translation of Bcl-xL mRNA, a well known target of Pdcd4 repression. By characterizing CRL3(IBTK) as a novel ubiquitin ligase, this study provides new insights into regulatory mechanisms of cellular pathways, such as the Pdcd4-dependent translation of mRNAs.
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pisano
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Ceglia
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy cpalmieri@unicz.it.
authors.forename: Camillo
authors.initials: C
authors.lastname: Palmieri
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Vecchio
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Fiume
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Annamaria
authors.initials: A
authors.lastname: de Laurentiis
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Selena
authors.initials: S
authors.lastname: Mimmi
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Falcone
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Iaccino
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Annarita
authors.initials: A
authors.lastname: Scialdone
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Pontoriero
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Francesca Fasanella
authors.initials: FF
authors.lastname: Masci
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Valea
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Shibu
authors.initials: S
authors.lastname: Krishnan
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gaspari
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Cuda
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy scala@unicz.it.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Scala
authors.affiliation: From the Department of Experimental and Clinical Medicine, University "Magna Graecia" of Catanzaro, 88100 Catanzaro, Italy quinto@unicz.it.
authors.forename: Ileana
authors.initials: I
authors.lastname: Quinto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020816:Amino Acid Motifs; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006706:Homeostasis; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016086:Lentivirus / Q000378:metabolism; D013058:Mass Spectrometry; D051379:Mice; D008969:Molecular Sequence Data; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D012689:Sequence Homology, Nucleic Acid; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C437966:IBtk protein, human; D047908:Intracellular Signaling Peptides and Proteins; C114487:PDCD4 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D025801:Ubiquitin; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex; D005978:Glutathione
keywords: E3 ubiquitin ligase; IBtk; Pdcd4; serum; translation regulation; tumor suppressor gene; ubiquitylation (ubiquitination)