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

Oncogene volume 37, pages 2806–2816 (2018)Cite this article

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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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References

  1. Bruhn RMR. Human lymphotropic viruses: HTLV-1 and HTLV-2. In: Richman DWR, editor. Clinical virology. 4th ed. Washington, DC: AM Press; 2017. p. 771–94.

    Google Scholar 

  2. Ciminale V, Rende F, Bertazzoni U, Romanelli MG. HTLV-1 and HTLV-2: highly similar viruses with distinct oncogenic properties. Front Microbiol. 2014;5:398.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wang TG, Ye J, Lairmore MD, Green PL. In vitro cellular tropism of human T cell leukemia virus type 2. AIDS Res Hum Retrovir. 2000;16:1661–8.

    Article  CAS  PubMed  Google Scholar 

  4. Xie L, Green PL. Envelope is a major viral determinant of the distinct in vitro cellular transformation tropism of human T-cell leukemia virus type 1 (HTLV-1) and HTLV-2. J Virol. 2005;79:14536–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Currer R, Van Duyne R, Jaworski E, Guendel I, Sampey G, Das R, et al. HTLV tax: a fascinating multifunctional co-regulator of viral and cellular pathways. Front Microbiol. 2012;3:406.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhao T, Matsuoka M. HBZ and its roles in HTLV-1 oncogenesis. Front Microbiol. 2012;3:247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mesnard JM, Barbeau B, Cesaire R, Peloponese JM. Roles of HTLV-1 basic Zip factor (HBZ) in viral chronicity and leukemic transformation. potential new therapeutic approaches to prevent and treat HTLV-1-related diseases. Viruses. 2015;7:6490–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Journo C, Douceron E, Mahieux R. HTLV gene regulation: because size matters, transcription is not enough. Future Microbiol. 2009;4:425–40.

    Article  CAS  PubMed  Google Scholar 

  9. Kfoury Y, Nasr R, Journo C, Mahieux R, Pique C, Bazarbachi A. The multifaceted oncoprotein Tax: subcellular localization, posttranslational modifications, and NF-kappaB activation. Adv Cancer Res. 2012;113:85–120.

    Article  CAS  PubMed  Google Scholar 

  10. Watanabe T. Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1-infected T cells. Blood. 2017;129:1071–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yamano Y, Sato T. Clinical pathophysiology of human T-lymphotropic virus-type 1-associated myelopathy/tropical spastic paraparesis. Front Microbiol. 2012;3:389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gaudray G, Gachon F, Basbous J, Biard-Piechaczyk M, Devaux C, Mesnard JM. The complementary strand of the human T-cell leukemia virus type 1 RNA genome encodes a bZIP transcription factor that down-regulates viral transcription. J Virol. 2002;76:12813–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Satou Y, Yasunaga J, Zhao T, Yoshida M, Miyazato P, Takai K, et al. HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo. PLoS Pathog. 2011;7:e1001274.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Giam CZ, Semmes OJ. HTLV-1 infection and adult T-cell leukemia/lymphoma-A tale of two proteins: Tax and HBZ. Viruses. 2016;8:E161. https://doi.org/10.3390/v8060161.

    Article  CAS  PubMed  Google Scholar 

  15. Nicot C. HTLV-I Tax-mediated inactivation of cell cycle checkpoints and DNA repair pathways contribute to cellular transformation: ‘A Random Mutagenesis Model’. J Cancer Sci 2015; 2. https://doi.org/10.13188/2377-9292.1000009.

  16. Shirinian M, Kambris Z, Hamadeh L, Grabbe C, Journo C, Mahieux R, et al. A transgenic Drosophila melanogaster model to study human T-lymphotropic virus oncoprotein Tax-1-driven transformation in vivo. J Virol. 2015;89:8092–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. El Hajj H, El-Sabban M, Hasegawa H, Zaatari G, Ablain J, Saab ST, et al. Therapy-induced selective loss of leukemia-initiating activity in murine adult T cell leukemia. J Exp Med. 2010;207:2785–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Halin M, Douceron E, Clerc I, Journo C, Ko NL, Landry S, et al. Human T-cell leukemia virus type 2 produces a spliced antisense transcript encoding a protein that lacks a classic bZIP domain but still inhibits Tax2-mediated transcription. Blood. 2009;114:2427–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Douceron E, Kaidarova Z, Miyazato P, Matsuoka M, Murphy EL, Mahieux R. HTLV-2 APH-2 expression is correlated with proviral load but APH-2 does not promote lymphocytosis. J Infect Dis. 2012;205:82–6.

    Article  CAS  PubMed  Google Scholar 

  20. Yin H, Kannian P, Dissinger N, Haines R, Niewiesk S, Green PL. Human T-cell leukemia virus type 2 antisense viral protein 2 is dispensable for in vitro immortalization but functions to repress early virus replication in vivo. J Virol. 2012;86:8412–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Panfil AR, Dissinger NJ, Howard CM, Murphy BM, Landes K, Fernandez SA, et al. Functional comparison of HBZ and the related APH-2 protein provides insight into human T-cell leukemia virus type 1 pathogenesis. J Virol. 2016;90:3760–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hivin P, Basbous J, Raymond F, Henaff D, Arpin-Andre C, Robert-Hebmann V, et al. The HBZ-SP1 isoform of human T-cell leukemia virus type I represses JunB activity by sequestration into nuclear bodies. Retrovirology. 2007;4:14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Lowrey AJ, Cramblet W, Bentz GL. Viral manipulation of the cellular sumoylation machinery. Cell Commun Signal. 2017;15:27.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Everett RD, Boutell C, Hale BG. Interplay between viruses and host sumoylation pathways. Nat Rev Microbiol. 2013;11:400–11.

    Article  CAS  PubMed  Google Scholar 

  25. Nasr R, Chiari E, El-Sabban M, Mahieux R, Kfoury Y, Abdulhay M, et al. Tax ubiquitylation and sumoylation control critical cytoplasmic and nuclear steps of NF-kappaB activation. Blood. 2006;107:4021–9.

    Article  CAS  PubMed  Google Scholar 

  26. Pene S, Waast L, Bonnet A, Benit L, Pique C. A non-SUMOylated tax protein is still functional for NF-kappaB pathway activation. J Virol. 2014;88:10655–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dassouki Z, Sahin U, El Hajj H, Jollivet F, Kfoury Y, Lallemand-Breitenbach V, et al. ATL response to arsenic/interferon therapy is triggered by SUMO/PML/RNF4-dependent Tax degradation. Blood. 2015;125:474–82.

    Article  CAS  PubMed  Google Scholar 

  28. Sahin U, Ferhi O, Carnec X, Zamborlini A, Peres L, Jollivet F, et al. Interferon controls SUMO availability via the Lin28 and let-7 axis to impede virus replication. Nat Commun. 2014;5:4187.

    Article  CAS  PubMed  Google Scholar 

  29. Journo C, Bonnet A, Favre-Bonvin A, Turpin J, Vinera J, Cote E, et al. Human T cell leukemia virus type 2 tax-mediated NF-kappaB activation involves a mechanism independent of Tax conjugation to ubiquitin and SUMO. J Virol. 2013;87:1123–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Komatsu T, Nagata K, Wodrich H. The role of nuclear antiviral factors against invading DNA viruses: the immediate fate of incoming viral genomes. Viruses. 2016;8:E290. https://doi.org/10.3390/v8100290.

    Article  CAS  PubMed  Google Scholar 

  31. Shiio Y, Rose DW, Aur R, Donohoe S, Aebersold R, Eisenman RN. Identification and characterization of SAP25, a novel component of the mSin3 corepressor complex. Mol Cell Biol. 2006;26:1386–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kadamb R, Mittal S, Bansal N, Batra H, Saluja D. Sin3: insight into its transcription regulatory functions. Eur J Cell Biol. 2013;92:237–46.

    Article  CAS  PubMed  Google Scholar 

  33. Jean MJ, Power D, Kong W, Huang H, Santoso N, Zhu J. Identification of HIV-1 Tat-associated proteins contributing to HIV-1 transcription and latency. Viruses. 2017;9:E67. https://doi.org/10.3390/v9040067.

    Article  PubMed  Google Scholar 

  34. Khan MM, Nomura T, Kim H, Kaul SC, Wadhwa R, Shinagawa T, et al. Role of PML and PML-RARalpha in Mad-mediated transcriptional repression. Mol Cell. 2001;7:1233–43.

    Article  CAS  PubMed  Google Scholar 

  35. Cachat A, Chevalier SA, Alais S, Ko NL, Ratner L, Journo C, et al. Alpha interferon restricts human T-lymphotropic virus type 1 and 2 de novo infection through PKR activation. J Virol. 2013;87:13386–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Regad T, Saib A, Lallemand-Breitenbach V, Pandolfi PP, de The H, Chelbi-Alix MK. PML mediates the interferon-induced antiviral state against a complex retrovirus via its association with the viral transactivator. EMBO J. 2001;20:3495–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ivanschitz L, Takahashi Y, Jollivet F, Ayrault O, Le Bras M, de The H. PML IV/ARF interaction enhances p53 SUMO-1 conjugation, activation, and senescence. Proc Natl Acad Sci USA. 2015;112:14278–83.

    Article  CAS  PubMed  Google Scholar 

  38. Thebault S, Basbous J, Hivin P, Devaux C, Mesnard JM. HBZ interacts with JunD and stimulates its transcriptional activity. FEBS Lett. 2004;562:165–70.

    Article  CAS  PubMed  Google Scholar 

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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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Author notes

  1. These authors contributed equally: Chloé Journo and Renaud Mahieux.

Authors and Affiliations

  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

    Louise Dubuisson, Florence Lormières, Jocelyn Turpin, Amandine Pasquier, Estelle Douceron, Anaïs Oliva, Chloé Journo & Renaud Mahieux

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

    Louise Dubuisson, Florence Lormières, Jocelyn Turpin, Amandine Pasquier, Estelle Douceron, Anaïs Oliva, Chloé Journo & Renaud Mahieux

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

    Stefania Fochi

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

    Ali Bazarbachi

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

    Ali Bazarbachi

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

    Valérie Lallemand-Breitenbach & Hugues De Thé

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Correspondence to Chloé Journo or Renaud Mahieux.

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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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