title: Human T-cell leukemia virus type 1 (HTLV-1) tax requires CADM1/TSLC1 for inactivation of the NF-κB inhibitor A20 and constitutive NF-κB signaling.
abstract: Persistent activation of NF-κB by the Human T-cell leukemia virus type 1 (HTLV-1) oncoprotein, Tax, is vital for the development and pathogenesis of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). K63-linked polyubiquitinated Tax activates the IKK complex in the plasma membrane-associated lipid raft microdomain. Tax also interacts with TAX1BP1 to inactivate the NF-κB negative regulatory ubiquitin-editing A20 enzyme complex. However, the molecular mechanisms of Tax-mediated IKK activation and A20 protein complex inactivation are poorly understood. Here, we demonstrated that membrane associated CADM1 (Cell adhesion molecule1) recruits Ubc13 to Tax, causing K63-linked polyubiquitination of Tax, and IKK complex activation in the membrane lipid raft. The c-terminal cytoplasmic tail containing PDZ binding motif of CADM1 is critical for Tax to maintain persistent NF-κB activation. Finally, Tax failed to inactivate the NF-κB negative regulator ubiquitin-editing enzyme A20 complex, and activate the IKK complex in the lipid raft in absence of CADM1. Our results thus indicate that CADM1 functions as a critical scaffold molecule for Tax and Ubc13 to form a cellular complex with NEMO, TAX1BP1 and NRP, to activate the IKK complex in the plasma membrane-associated lipid rafts, to inactivate NF-κB negative regulators, and maintain persistent NF-κB activation in HTLV-1 infected cells.
authors.affiliation: Department of Microbiology and Immunology, Viral Oncology Program, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, Miami, Florida, United States of America.
authors.forename: Rajeshree
authors.initials: R
authors.lastname: Pujari
authors.affiliation: Department of Microbiology and Immunology, Viral Oncology Program, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, Miami, Florida, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Hunte
authors.affiliation: Department of Microbiology and Immunology, Viral Oncology Program, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, Miami, Florida, United States of America.
authors.forename: Remy
authors.initials: R
authors.lastname: Thomas
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, United Kingdom.
authors.forename: Louise
authors.initials: L
authors.lastname: van der Weyden
authors.affiliation: Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: Dan
authors.initials: D
authors.lastname: Rauch
authors.affiliation: Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: Lee
authors.initials: L
authors.lastname: Ratner
authors.affiliation: Department of Biochemistry and Molecular Biology, Colorado State University, Fort Collins, Colorado, United States of America.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Nyborg
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Viral Oncology Program, Sylvester Comprehensive Cancer Center, and Center for AIDS Research and Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Ramos
authors.affiliation: Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Chuo-ku, Kobe, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Takai
authors.affiliation: Department of Microbiology and Immunology, Viral Oncology Program, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, Miami, Florida, United States of America.
authors.forename: Noula
authors.initials: N
authors.lastname: Shembade
mesh_terms: D000818:Animals; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006800:Deltaretrovirus Infections / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D016355:Genes, pX / Q000502:physiology*; D015368:Human T-lymphotropic virus 1; D006801:Humans; D015151:Immunoblotting; D007136:Immunoglobulins / Q000378:metabolism*; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D019169:Jurkat Cells; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D016328:NF-kappa B / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D014162:Transfection; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D044763:Ubiquitin-Conjugating Enzymes / Q000378:metabolism
chemical_list: C403514:CADM1 protein, human; C498598:Cadm1 protein, mouse; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D004268:DNA-Binding Proteins; D007136:Immunoglobulins; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009687:Nuclear Proteins; C471607:UBE2N protein, human; C514982:Ube2n protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse