title: Ubiquitination and sumoylation of the HTLV-2 Tax-2B protein regulate its NF-κB activity: a comparative study with the HTLV-1 Tax-1 protein.
abstract: BACKGROUND
  Retroviruses HTLV-1 and HTLV-2 have homologous genomic structures but differ significantly in pathogenicity. HTLV-1 is associated with Adult T cell Leukemia (ATL), whereas infection by HTLV-2 has no association with neoplasia. Transformation of T lymphocytes by HTLV-1 is linked to the capacity of its oncoprotein Tax-1 to alter cell survival and cell cycle control mechanisms. Among these functions, Tax-1-mediated activation of cellular gene expression via the NF-κB pathway depends on Tax-1 post-translational modifications by ubiquitination and sumoylation. The Tax-2 protein of HTLV-2B (Tax-2B) is also modified by ubiquitination and sumoylation and activates the NF-κB pathway to a level similar to that of Tax-1. The present study aims to understand whether ubiquitination and sumoylation modifications are involved in Tax-2B-mediated activation of the NF-κB pathway.
  
  
  RESULTS
  The comparison of Tax-1 and Tax-2B lysine to arginine substitution mutants revealed conserved patterns and levels of ubiquitination with notable difference in the lysine usage for sumoylation. Neither Tax-1 nor Tax-2B ubiquitination and sumoylation deficient mutants could activate the NF-κB pathway and fusion of ubiquitin or SUMO-1 to the C-terminus of the ubiquitination and sumoylation deficient Tax-2B mutant strikingly restored transcriptional activity. In addition, ubiquitinated forms of Tax-2B colocalized with RelA and IKKγ in prominent cytoplasmic structures associated with the Golgi apparatus, whereas colocalization of Tax-2B with the RelA subunit of NF-κB and the transcriptional coactivator p300 in punctate nuclear structures was dependent on Tax-2B sumoylation, as previously observed for Tax-1.
  
  
  CONCLUSIONS
  Both Tax-1 and Tax-2 activate the NF-κB pathway via similar mechanisms involving ubiquitination and sumoylation. Therefore, the different transforming potential of HTLV-1 and HTLV-2 is unlikely to be related to different modes of activation of the canonical NF-κB pathway.
authors.affiliation: Department of Life and Reproduction Sciences, Section of Biology and Genetics, University of Verona, Strada Le Grazie 8, 37134, Verona, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Turci
authors.forename: Julie
authors.initials: J
authors.lastname: Lodewick
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Di Gennaro
authors.forename: Anne Sophie
authors.initials: AS
authors.lastname: Rinaldi
authors.forename: Oriano
authors.initials: O
authors.lastname: Marin
authors.forename: Erica
authors.initials: E
authors.lastname: Diani
authors.forename: Carla
authors.initials: C
authors.lastname: Sampaio
authors.forename: Françoise
authors.initials: F
authors.lastname: Bex
authors.forename: Umberto
authors.initials: U
authors.lastname: Bertazzoni
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Romanelli
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002467:Cell Nucleus / Q000378:metabolism; D017124:Conserved Sequence; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D016356:Gene Products, tax / Q000378:metabolism*; D057809:HEK293 Cells; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D015368:Human T-lymphotropic virus 1 / Q000502:physiology*; D015367:Human T-lymphotropic virus 2 / Q000502:physiology*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D021381:Protein Transport; D058207:Sumoylation; D015533:Transcriptional Activation; D054875:Ubiquitination
chemical_list: D016356:Gene Products, tax; D016328:NF-kappa B; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051550:I-kappa B Kinase