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Nucleolin Is Required for an Efficient Herpes Simplex Virus Type 1 Infection

Aleth Callé,^1,2,3 Iva Ugrinova,^4,5, Alberto L. Epstein,^1,2,3 Philippe Bouvet,^4,5 Jean-Jacques Diaz,^1,2,3 and Anna Greco^1,2,3*

Université de Lyon, Lyon F-69003, France,¹ Université Lyon 1, Lyon F-69003, France,² CNRS, UMR5534, Centre de Génétique Moléculaire et Cellulaire, 16 rue Dubois, Villeurbanne, F-69622, France,³ Université de Lyon, Ecole Normale Supérieure de Lyon, CNRS USR 3010, Laboratoire Joliot-Curie, 46 Allée d'Italie, Lyon, France,⁴ Laboratoire de Biologie Moléculaire de la Cellule, CNRS UMR 5239, IFR128 Biosciences, 46 Allée d'Italie, Lyon, France⁵

Received 11 January 2008/ Accepted 27 February 2008

Productive infection by herpes simplex virus type 1 (HSV-1), which occurs in the host cell nucleus, is accompanied by dramatic modifications of the nuclear architecture, including profound alterations of nucleolar morphology. Here, we show that the three most abundant nucleolar proteins—nucleolin, B23, and fibrillarin—are redistributed out of the nucleoli as a consequence of HSV-1 infection. We show that the amount of nucleolin increases progressively during the course of infection. We demonstrate for the first time that a nucleolar protein, i.e., nucleolin, colocalizes with ICP8 in the viral replication compartments, at the time when viral replication is effective, suggesting an involvement of nucleolin in the HSV-1 DNA replication process. At later times of infection, a granular form of nucleolin localizes to the cytoplasm, in structures that display the characteristic features of aggresomes, indicating that this form of nucleolin is very probably destined for degradation. The delocalization of nucleolin from the nucleoli requires the viral ICP4 protein or a factor(s) whose expression involves ICP4. Using small interfering RNA technology, we show that viral replication requires a high level of nucleolin expression, demonstrating for the first time a direct role for a nucleolar protein in herpes simplex virus biology.

Published ahead of print on 5 March 2008.

Present address: Institute of Molecular Biology, BAS, Acad G. Bonchev str. B121, 1113 Sofia, Bulgaria.