Abstract
Since the identification of the antisense protein of HTLV-2 (APH-2) and the demonstration that APH-2 mRNA is expressed in vivo in most HTLV-2 carriers, much effort has been dedicated to the elucidation of similarities and/or differences between APH-2 and HBZ, the antisense protein of HTLV-1. Similar to HBZ, APH-2 negatively regulates HTLV-2 transcription. However, it does not promote cell proliferation. In contrast to HBZ, APH-2 half-life is very short. Here, we show that APH-2 is addressed to PML nuclear bodies in T-cells, as well as in different cell types. Covalent SUMOylation of APH-2 is readily detected, indicating that APH-2 might be addressed to the PML nuclear bodies in a SUMO-dependent manner. We further show that silencing of PML increases expression of APH-2, while expression of HBZ is unaffected. On the other hand, SUMO-1 overexpression leads to a specific loss of APH-2 expression that is restored upon proteasome inhibition. Furthermore, the carboxy-terminal LAGLL motif of APH-2 is responsible for both the targeting of the protein to PML nuclear bodies and its short half-life. Taken together, these observations indicate that natural APH-2 targeting to PML nuclear bodies induces proteasomal degradation of the viral protein in a SUMO-dependent manner. Hence, this study deciphers the molecular and cellular bases of APH-2 short half-life in comparison to HBZ and highlights key differences in the post-translational mechanisms that control the expression of both proteins.
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Acknowledgements
We thank the microscopy facility team of the Lyon SFR Biosciences. R.M., C.J., and F.L. are supported by ENS Lyon. L.D. is supported by ANR. J.T. was supported by the Fondation ARC pour la Recherche sur le Cancer. E.D. was supported by the Ministère de la Recherche. This work was supported by ARC and La Ligue Contre le Cancer “programme Équipe Labellisée” and INSERM.
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Dubuisson, L., Lormières, F., Fochi, S. et al. Stability of HTLV-2 antisense protein is controlled by PML nuclear bodies in a SUMO-dependent manner. Oncogene 37, 2806–2816 (2018). https://doi.org/10.1038/s41388-018-0163-x
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DOI: https://doi.org/10.1038/s41388-018-0163-x
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