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Rabies virus P and small P products interact directly with PML and reorganize PML nuclear bodies

Oncogene volume 21, pages 7957–7970 (2002)Cite this article

Abstract

The interferon-induced promyelocytic leukaemia (PML) protein localizes both in the nucleoplasm and in matrix-associated multi-protein complexes known as nuclear bodies (NBs). NBs are disorganized in acute promyelocytic leukaemia or during some viral infections, suggesting that PML NBs could be a part of cellular defense mechanism. Rabies virus, a member of the rhabdoviridae family, replicates in the cytoplasm. Rabies phosphoprotein P and four other amino-terminally truncated products (P2, P3, P4, P5) are all translated from P mRNA. P and P2 are located in the cytoplasm, whereas P3, P4 and P5 are found mostly in the nucleus. Infection with rabies virus reorganized PML NBs. PML NBs became larger and appeared as dense aggregates when analysed by confocal or electron microscopy, respectively. The expression of P sequesters PML in the cytoplasm where both proteins colocalize, whereas that of P3 results in an increase in PML body size, as observed in infected cells. The P and P3 interacted directly in vivo and in vitro with PML. The C-terminal domain of P and the PML RING finger seem to be involved in this binding. Moreover, PML−/− primary mouse embryonic fibroblasts expressed viral proteins at a higher level and produced 20 times more virus than wild-type cells, suggesting that the absence of all PML isoforms resulted in an increase in rabies virus replication.

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Abbreviations

NBs:

nuclear bodies

PML:

promyelocytic leukaemia

VSV:

vesicular stomatitis virus

M.O.I.:

multiplicity of infection

IFN:

interferon

SUMO:

small ubiquitin modifier

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Acknowledgements

We acknowledge E Duprez and P Freemont for the RING finger PML Cys 57,60 mutant. The help of M Schmid and Z Mishal with the confocal microscopy analysis was greatly appreciated. We would like to thank Magalis Berges for technical assistance. This work was supported by grants from the Centre National pour la Recherche Scientifique, the Association pour la Recherche sur le Cancer (ARC) and the Fondation de la Recherche Médicale. T Regad was supported by a fellowship from ARC.

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Authors and Affiliations

  1. UMRCNRS2472, Gif sur Yvette, 91198, France

    Danielle Blondel & Nicolas Poisson

  2. UPRCNRS9045, Institut Lwoff, 7 rue Guy Moquet, Villejuif, 94801, France

    Tarick Regad, Benjamen Pavie & Mounira K Chelbi-Alix

  3. UPRCNRS1983, Institut Lwoff, 7 rue Guy Moquet, Villejuif, 94801, France

    Francis Harper

  4. Memorial Sloan-Kettering Cancer Center, York Avenue, New York, 1275, USA

    Pier Paolo Pandolfi

  5. UPRCNRS9051, Hôpital St Louis, Paris, 75475, France

    Hugues de Thé

Authors
  1. Danielle Blondel
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  2. Tarick Regad
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Correspondence to Mounira K Chelbi-Alix.

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Blondel, D., Regad, T., Poisson, N. et al. Rabies virus P and small P products interact directly with PML and reorganize PML nuclear bodies. Oncogene 21, 7957–7970 (2002). https://doi.org/10.1038/sj.onc.1205931

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