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The HTLV-1 Tax protein inhibits formation of stress granules by interacting with histone deacetylase 6

Oncogene volume 30, pages 4050–4062 (2011)Cite this article

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Abstract

Human T cell leukemia virus type-1 (HTLV-1) is the causative agent of a fatal adult T-cell leukemia. Through deregulation of multiple cellular signaling pathways the viral Tax protein has a pivotal role in T-cell transformation. In response to stressful stimuli, cells mount a cellular stress response to limit the damage that environmental forces inflict on DNA or proteins. During stress response, cells postpone the translation of most cellular mRNAs, which are gathered into cytoplasmic mRNA-silencing foci called stress granules (SGs) and allocate their available resources towards the production of dedicated stress-management proteins. Here we demonstrate that Tax controls the formation of SGs and interferes with the cellular stress response pathway. In agreement with previous reports, we observed that Tax relocates from the nucleus to the cytoplasm in response to environmental stress. We found that the presence of Tax in the cytoplasm of stressed cells prevents the formation of SGs and counteracts the shutoff of specific host proteins. Unexpectedly, nuclear localization of Tax promotes spontaneous aggregation of SGs, even in the absence of stress. Mutant analysis revealed that the SG inhibitory capacity of Tax is independent of its transcriptional abilities but relies on its interaction with histone deacetylase 6, a critical component of SGs. Importantly, the stress-protective effect of Tax was also observed in the context of HTLV-1 infected cells, which were shown to be less prone to form SGs and undergo apoptosis under arsenite exposure. These observations identify Tax as the first virally encoded inhibitory component of SGs and unravel a new strategy developed by HTLV-1 to deregulate normal cell processes. We postulate that inhibition of the stress response pathway by Tax would favor cell survival under stressful conditions and may have an important role in HTLV-1-induced cellular transformation.

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Acknowledgements

We thank all members of the Dequiedt laboratory for helpful and stimulating discussions. This work was supported by the Belgian National Fund for Scientific Research, the Télévie (7.4613.09), the Belgian Foundation Against Cancer, the Interuniversity Attraction Poles Program–Belgian Science Policy (IUAP-BELSPO PVI/28). FD and JCT are Research Associates, MB is a Postdoctoral Researcher, SL is a FRIA Fellow and R.K. is a Research Director of the Belgian National Fund for Scientific Research.

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  1. S Legros and M Boxus: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Molecular and Cellular Biology, Gembloux Agro-Bio Tech, University of Liège (ULg), Gembloux, Belgium

    S Legros, M Boxus, R Kettmann, J C Twizere & F Dequiedt

  2. Center for Molecular Virology, IBMM, Free University of Brussels (ULB), 12 rue des Professeurs Jeener et Brachet, Gosselies, Belgium

    J S Gatot & C Van Lint

  3. Center of Molecular Biology of the gene, IBMM, Free University of Brussels (ULB), 12 rue des Professeurs Jeener et Brachet, Gosselies, Belgium

    V Kruys

  4. Laboratory of Protein Signaling and Interactions, GIGA-Research, University of Liège (ULg), Liège, Belgium

    J C Twizere & F Dequiedt

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Legros, S., Boxus, M., Gatot, J. et al. The HTLV-1 Tax protein inhibits formation of stress granules by interacting with histone deacetylase 6. Oncogene 30, 4050–4062 (2011). https://doi.org/10.1038/onc.2011.120

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