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Dengue virus M protein contains a proapoptotic sequence referred to as ApoptoM

Olga Kalinina^1,

Marie-Pierre Courageot^1,

¹ Unité Postulante des Interactions Moléculaires Flavivirus-Hôtes, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15, France
² Plate-Forme de Cytométrie, Institut Pasteur, 25 rue du Dr Roux, 75724 Paris Cedex 15, France
³ Unité de Biologie des Infections Virales Emergentes, Institut Pasteur, Lyon, France

Correspondence
Philippe Desprès
pdespres{at}pasteur.fr

The induction of apoptotic cell death is a prominent cytopathic effect of dengue (DEN) viruses. One of the key questions to be addressed is which viral components induce apoptosis in DEN virus-infected cells. This study investigated whether the small membrane (M) protein was involved in the induction of apoptosis by DEN virus. This was addressed by using a series of enhanced green fluorescent protein-fused DEN proteins. Evidence is provided that intracellular production of the M ectodomains (residues M-1 to M-40) of all four DEN serotypes triggered apoptosis in host cells such as mouse neuroblastoma Neuro 2a and human hepatoma HepG2 cells. The M ectodomains of the wild-type strains of Japanese encephalitis, West Nile and yellow fever viruses also had proapoptotic properties. The export of the M ectodomain from the Golgi apparatus to the plasma membrane appeared to be essential for the initiation of apoptosis. The study found that anti-apoptosis protein Bcl-2 protected HepG2 cells against the death-promoting activity of the DEN M ectodomain. This suggests that the M ectodomain exerts its cytotoxic effects by activating a mitochondrial apoptotic pathway. The cytotoxicity of the DEN M ectodomain reflected the intrinsic proapoptotic properties of the nine carboxy-terminal amino acids (residues M-32 to M-40) designated ApoptoM. Residue M-36 was unique in that it modulated the death-promoting activity of the M ectodomain. Defining the ApoptoM-activated signalling pathways leading to apoptosis will provide the basis for studying how the M protein might play a key role in the fate of the flavivirus-infected cells.

Present address: Pasteur Institute of Saint Petersburg, U1 Mira 14, 197101 Saint Petersburg, Russia.

Present address: Laboratoire des Biomembranes et Messagers Cellulaires, CNRS-UMR 8619, Université Paris XI, Orsay, France.

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