title: Human T cell leukemia virus type 2 tax-mediated NF-κB activation involves a mechanism independent of Tax conjugation to ubiquitin and SUMO.
abstract: Permanent activation of the NF-κB pathway by the human T cell leukemia virus type 1 (HTLV-1) Tax (Tax1) viral transactivator is a key event in the process of HTLV-1-induced T lymphocyte immortalization and leukemogenesis. Although encoding a Tax transactivator (Tax2) that activates the canonical NF-κB pathway, HTLV-2 does not cause leukemia. These distinct pathological outcomes might be related, at least in part, to distinct NF-κB activation mechanisms. Tax1 has been shown to be both ubiquitinated and SUMOylated, and these two modifications were originally proposed to be required for Tax1-mediated NF-κB activation. Tax1 ubiquitination allows recruitment of the IKK-γ/NEMO regulatory subunit of the IKK complex together with Tax1 into centrosome/Golgi-associated cytoplasmic structures, followed by activation of the IKK complex and RelA/p65 nuclear translocation. Herein, we compared the ubiquitination, SUMOylation, and acetylation patterns of Tax2 and Tax1. We show that, in contrast to Tax1, Tax2 conjugation to endogenous ubiquitin and SUMO is barely detectable while both proteins are acetylated. Importantly, Tax2 is neither polyubiquitinated on lysine residues nor ubiquitinated on its N-terminal residue. Consistent with these observations, Tax2 conjugation to ubiquitin and Tax2-mediated NF-κB activation is not affected by overexpression of the E2 conjugating enzyme Ubc13. We further demonstrate that a nonubiquitinable, non-SUMOylable, and nonacetylable Tax2 mutant retains a significant ability to activate transcription from a NF-κB-dependent promoter after partial activation of the IKK complex and induction of RelA/p65 nuclear translocation. Finally, we also show that Tax2 does not interact with TRAF6, a protein that was shown to positively regulate Tax1-mediated activation of the NF-κB pathway.
authors.affiliation: Oncogenèse Rétrovirale, INSERM U758, Lyon, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Journo
authors.forename: Amandine
authors.initials: A
authors.lastname: Bonnet
authors.forename: Arnaud
authors.initials: A
authors.lastname: Favre-Bonvin
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Turpin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Vinera
authors.forename: Emilie
authors.initials: E
authors.lastname: Côté
authors.forename: Sébastien Alain
authors.initials: SA
authors.lastname: Chevalier
authors.forename: Youmna
authors.initials: Y
authors.lastname: Kfoury
authors.forename: Ali
authors.initials: A
authors.lastname: Bazarbachi
authors.forename: Claudine
authors.initials: C
authors.lastname: Pique
authors.forename: Renaud
authors.initials: R
authors.lastname: Mahieux
mesh_terms: D000107:Acetylation; D016356:Gene Products, tax / Q000378:metabolism*; D006367:HeLa Cells; D015367:Human T-lymphotropic virus 2 / Q000472:pathogenicity*; D006801:Humans; D019169:Jurkat Cells; D016328:NF-kappa B / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*; D058207:Sumoylation; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: D016356:Gene Products, tax; D016328:NF-kappa B; D025841:Small Ubiquitin-Related Modifier Proteins; D025801:Ubiquitin; C514970:tax protein, Human T-lymphotrophic virus 1; C514971:tax protein, Human T-lymphotrophic virus 2