Stability of HTLV-2 antisense protein is controlled by PML nuclear bodies in a SUMO-dependent manner.


Oncogene. 2018 Mar 6. doi: 10.1038/s41388-018-0163-x. [Epub ahead of print]


Dubuisson L1,2, Lormières F1,2, Fochi S3, Turpin J1,2, Pasquier A1,2, Douceron E1,2, Oliva A1,2, Bazarbachi A4,5, Lallemand-Breitenbach V6, De Thé H6, Journo C1,2, Mahieux R1,2.

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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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Affiliations des auteurs:

1 International Center for Research in Infectiology, Retroviral Oncogenesis Laboratory, INSERM U1111 – Université Claude Bernard Lyon 1, CNRS, UMR5308, Ecole Normale Supérieure de Lyon, Université Lyon, F-69007, Lyon, France.

2 Equipe labellisée “Ligue Nationale Contre le Cancer”, Lyon, France.

3 Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

4 Department of Internal Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.

5 Department of Anatomy, Cell Biology and Physiological Sciences, American University of Beirut, Beirut, Lebanon.

6 Collège de France – Paris Sorbonne, Inserm U944-CNRS 7212 – Université Paris Diderot, Lettre – 11 place Marcelin Berthelot, 75231, Paris Cedex 05, France.