Molecular Mechanisms of NF-kappaB Activation by the HTLV-I Oncoprotein Tax: Role of Post Translational Protein Modification.

Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of mature activated T-cells caused by human T cell lymphotropic virus type I (HTLV-I). The Tax viral oncoprotein plays a crucial role in the proliferation and transformation of HTLV-I infected T lymphocytes through various mechanisms, chiefly through activation of the NF-kappaB pathway. We found that ubiquitin binding to Tax C-terminal lysines in the cytoplasm is critical for Tax binding to the IkappaB kinase (IKK) complex and subsequent nuclear translocation of NF-kappaB. Conversely, we demonstrate that the same Tax lysines are modified by SUMO binding in the nucleus, an event required for the formation of Tax nuclear bodies and full NF-kappaB transcriptional activation. We further show that ubiquitylated Tax is not associated with active cytosolic IKK subunits, but binds endogenous IKK subunits and targets them to the centrosome. Indeed, differential ubiquitylation of Tax results in different outcomes: K63-ubiquitylated Tax colocalizes at the centrosome with IKK, while K48-ubiquitylated Tax is degraded by the proteasome. Altogether, these results support a model in which K63-ubiquitylated Tax activates IKK in a centrosome-associated signalosome, leading to the production of Tax-free active cytoplasmic IKK. Thus, ubiquitylation and sumoylation of the same lysine residues of Tax regulate two essential steps controlling NF-kappaB activation, demonstrating how these posttranslational modifications can cooperate to promote Tax-induced transformation. These observations highlight an unsuspected cellular and biochemical complexity in Tax-induced NF-kappaB activation and represents ideal targets for the development of new drugs for ATL therapy.