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Open Access Research

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

Marco Turci1, Julie Lodewick2, Gianfranco Di Gennaro1, Anne Sophie Rinaldi2, Oriano Marin3, Erica Diani1, Carla Sampaio2, Françoise Bex2*, Umberto Bertazzoni1 and Maria Grazia Romanelli1

  • * Corresponding author: Françoise Bex fbex@ulb.ac.be

  • † Equal contributors

Author Affiliations

1 Department of Life and Reproduction Sciences, Section of Biology and Genetics, University of Verona, Strada Le Grazie 8, 37134, Verona, Italy

2 Institute for Microbiological Research J-M Wiame, Laboratory of Microbiology, Université Libre de Bruxelles, 1, Avenue E. Gryson, Brussels, Belgium

3 Department of Oncology and Surgical Sciences, University of Padova, Padova, Italy

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Retrovirology 2012, 9:102  doi:10.1186/1742-4690-9-102

Published: 7 December 2012

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.

Keywords:
HTLV-1; HTLV-2; Retrovirus; Tax; Oncoprotein; Leukemia; Post-translational modification; Ubiquitination; Sumoylation; NF-κB pathway