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Journal of Virology, September 2009, p. 8849-8858, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.00339-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Kaposi's Sarcoma-Associated Herpesvirus Protein LANA2 Disrupts PML Oncogenic Domains and Inhibits PML-Mediated Transcriptional Repression of the Survivin Gene {triangledown} ,{dagger}

Laura Marcos-Villar,1,2 Fernando Lopitz-Otsoa,3 Pedro Gallego,2 Cesar Muñoz-Fontela,4 José González-Santamaría,2 Michela Campagna,2 Gao Shou-Jiang,5 Manuel S. Rodriguez,3 and Carmen Rivas2*

Departamento Microbiología II, Facultad de Farmacia, Universidad Complutense de Madrid, Plaza Ramón y Cajal, 28040 Madrid, Spain,1 Centro Nacional de Biotecnología, CSIC, Campus Universidad Autónoma de Madrid, 28049 Madrid, Spain,2 Proteomics Unit, CICbioGUNE, CIBERehd and Biochemistry Department, University of the Basque Country, Technology Park of Bizkaia, Building 801A, 48160 Derio, Spain,3 Department of Oncological Sciences, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, New York 10029,4 Department of Pediatrics and Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 782285

Received 16 February 2009/ Accepted 15 June 2009

Infection by herpesviruses causes a dramatic disturbance of PML oncogenic domains (PODs) that has been suggested to be essential for viral lytic replication. Several proteins from Kaposi's sarcoma-associated herpesvirus (KSHV) have been tested as putative POD-disrupting factors with negative results. Here, we show that LANA2, a viral protein that is absolutely required for the viability and proliferation of KSHV-infected primary effusion lymphoma (PEL) cells, increases the levels of SUMO2-ubiquitin-modified PML and induces the disruption of PODs by a proteasome-mediated mechanism. In addition, we demonstrate that this disruption is largely dependent on both the integrity of a SUMO interaction motif in LANA2 and the lysine 160 from PML. Moreover, silencing of LANA2 expression in PEL cells by RNA interference led to an increase in the PML levels. Finally, we demonstrate that LANA2 relieves PML-mediated transcriptional repression of survivin, a protein that directly contributes to malignant progression of PEL. This represents the first example of inactivation of these important antiviral structures by KSHV.

* Corresponding author. Mailing address: Centro Nacional de Biotecnología, CSIC, Campus Universidad Autónoma de Madrid, Madrid 28049, Spain. Phone: 34 915855303. Fax: 34 915854506. E-mail: crivas{at}cnb.csic.es

{triangledown} Published ahead of print on 24 June 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, September 2009, p. 8849-8858, Vol. 83, No. 17
0022-538X/09/$08.00+0     doi:10.1128/JVI.00339-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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