Measles virus nucleoprotein induces cell-proliferation arrest and apoptosis through NTAIL-NR and NCORE-FcgammaRIIB1 interactions, respectively.
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: FcgammaRIIB and an uncharacterized nucleoprotein receptor (NR). MV-N is composed of two domains: NCORE (aa 1-400) and NTAIL (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 FcgammaRIIB1 was used as a model. Specific and exclusive NCORE-FcgammaRIIB1 and NTAIL-NR interactions were shown. Moreover, NTAIL 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. NCORE binding to HT144IIB1 cells primarily triggered caspase-3 activation, in contrast to HT144IIB1/IC- cells lacking the FcgammaRIIB1 intra-cytoplasmic tail, thus demonstrating the specific inhibitory effect of the NCORE-FcgammaRIIB1 interaction. MV-N- and NCORE-mediated apoptosis through FcgammaRIIB1 was inhibited by the pan-caspase inhibitor zVAD-FMK, indicating that apoptosis was dependent on caspase activation. By using NTAIL deletion proteins, it was also shown that the region of NTAIL 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.
Laine
D
D
Laboratoire d'Immunobiologie Fondamentale et Clinique, INSERM U503 and UCBL1, IFR128 BioSciences Lyon-Gerland, 21 Avenue Tony Garnier, 69365 Lyon Cedex 07, France.
Bourhis
J M
JM
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.
Longhi
S
S
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.
Flacher
M
M
Laboratoire d'Immunobiologie Fondamentale et Clinique, INSERM U503 and UCBL1, IFR128 BioSciences Lyon-Gerland, 21 Avenue Tony Garnier, 69365 Lyon Cedex 07, France.
Cassard
L
L
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.
Canard
B
B
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.
Sautès-Fridman
C
C
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.
Rabourdin-Combe
C
C
Laboratoire d'Immunobiologie Fondamentale et Clinique, INSERM U503 and UCBL1, IFR128 BioSciences Lyon-Gerland, 21 Avenue Tony Garnier, 69365 Lyon Cedex 07, France.
Valentin
H
H
Laboratoire d'Immunobiologie Fondamentale et Clinique, INSERM U503 and UCBL1, IFR128 BioSciences Lyon-Gerland, 21 Avenue Tony Garnier, 69365 Lyon Cedex 07, France.
D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D017353:Gene Deletion; D006801:Humans; D008459:Measles virus / Q000378:metabolism / Q000502:physiology*; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism*; D017452:Receptors, IgG / Q000378:metabolism*; D011991:Receptors, Virus / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
D015703:Antigens, CD; C080571:Fc gamma receptor IIB; D019590:Nucleocapsid Proteins; D009698:Nucleoproteins; D011956:Receptors, Cell Surface; D017452:Receptors, IgG; D011991:Receptors, Virus; D014764:Viral Proteins; C058314:nucleoprotein, Measles virus