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Measles virus nucleoprotein induces cell-proliferation arrest and apoptosis through N_TAIL–NR and N_CORE–FcRIIB1 interactions, respectively

D. Laine^1,

J. M. Bourhis^2,

H. Valentin^1,

¹ Laboratoire d'Immunobiologie Fondamentale et Clinique, INSERM U503 and UCBL1, IFR128 BioSciences Lyon-Gerland, 21 Avenue Tony Garnier, 69365 Lyon Cedex 07, France
² Architecture et Fonction des Macromolécules Biologiques, UMR 6098 CNRS et Universités d'Aix-Marseille I et II, ESIL, 163 Avenue de Luminy, Case 925, 13288 Marseille, France
³ Unité d'Immunologie Cellulaire et Clinique, INSERM U255 and Université Pierre et Marie Curie Paris VI, Centre de Recherche Biomédicales des Cordeliers, 15 rue de l'école de médecine, 75006 Paris, France

Correspondence
H. Valentin
helene.valentin{at}univ-lyon1.fr

Measles virus (MV) nucleoprotein (N) is a cytosolic protein that is released into the extracellular compartment after apoptosis and/or secondary necrosis of MV-infected cells in vitro. Thus, MV-N becomes accessible to inhibitory cell-surface receptors: FcRIIB and an uncharacterized nucleoprotein receptor (NR). MV-N is composed of two domains: N_CORE (aa 1–400) and N_TAIL (aa 401–525). To assess the contribution of MV-N domains and of these two receptors in suppression of cell proliferation, a human melanoma HT144 cell line expressing (HT144IIB1) or lacking FcRIIB1 was used as a model. Specific and exclusive N_CORE–FcRIIB1 and N_TAIL–NR interactions were shown. Moreover, N_TAIL binding to human NR predominantly led to suppression of cell proliferation by arresting cells in the G₀/G₁ phases of the cell cycle, rather than to apoptosis. N_CORE binding to HT144IIB1 cells primarily triggered caspase-3 activation, in contrast to HT144IIB1/IC^– cells lacking the FcRIIB1 intra-cytoplasmic tail, thus demonstrating the specific inhibitory effect of the N_CORE–FcRIIB1 interaction. MV-N- and N_CORE-mediated apoptosis through FcRIIB1 was inhibited by the pan-caspase inhibitor zVAD-FMK, indicating that apoptosis was dependent on caspase activation. By using N_TAIL deletion proteins, it was also shown that the region of N_TAIL responsible for binding to human NR and for cell growth arrest maps to one of the three conserved boxes (Box1, aa 401–420) found in N of Morbilliviruses. This work unveils novel mechanisms by which distinct domains of MV-N may display different immunosuppressive activities, thus contributing to our comprehension of the immunosuppressive state associated with MV infection. Finally, MV-N domains may be good tools to target tumour cell proliferation and/or apoptosis.

These authors contributed equally to this work.

Present address: Immunité et Infections Virales, Faculté de Médecine Lyon RTH Laennec, CNRS-UCBL UMR5537, 69372 Lyon Cedex 08, France.

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