title: The ubiquitin-specific protease USP7 modulates the replication of Kaposi's sarcoma-associated herpesvirus latent episomal DNA.
abstract: Kaposi's sarcoma herpesvirus (KSHV) belongs to the gamma-2 Herpesviridae and is associated with three neoplastic disorders: Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman's disease (MCD). The viral latency-associated nuclear antigen 1 (LANA) is expressed in all latently KSHV-infected cells and is involved in viral latent replication and maintenance of the viral genome. We show that LANA interacts with the ubiquitin-specific protease USP7 through its N-terminal TRAF (tumor necrosis factor [TNF] receptor-associated factor) domain. This interaction involves a short sequence (amino acids [aa] 971 to 986) within the C-terminal domain of LANA with strong similarities to the USP7 binding site of the Epstein-Barr virus (EBV) EBNA-1 protein. A LANA mutant with a deletion of the identified USP7 binding site showed an enhanced ability to replicate a plasmid containing the KSHV latent origin of replication but was comparable to the wild-type LANA (LANA WT) with regard to the regulation of viral and cellular promoters. Furthermore, the LANA homologues of two other gamma-2 herpesviruses, MHV68 and RRV, also recruit USP7. Our findings suggest that recruitment of USP7 to LANA could play a role in the regulation of viral latent replication. The recruitment of USP7, and its role in herpesvirus latent replication, previously described for the latent EBNA-1 protein of the gamma-1 herpesvirus (lymphocryptovirus) EBV (M. N. Holowaty et al., J. Biol. Chem. 278:29987-29994, 2003), may thereby be a conserved feature among gammaherpesvirus latent origin binding proteins.
authors.affiliation: Institut für Virologie, Medizinische Hochschule Hannover, Hannover, Germany.
authors.forename: Wiebke
authors.initials: W
authors.lastname: Jäger
authors.forename: Susann
authors.initials: S
authors.lastname: Santag
authors.forename: Magdalena
authors.initials: M
authors.lastname: Weidner-Glunde
authors.forename: Eva
authors.initials: E
authors.lastname: Gellermann
authors.forename: Semra
authors.initials: S
authors.lastname: Kati
authors.forename: Marcel
authors.initials: M
authors.lastname: Pietrek
authors.forename: Abel
authors.initials: A
authors.lastname: Viejo-Borbolla
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Schulz
mesh_terms: D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004279:DNA, Viral / Q000235:genetics* / Q000378:metabolism; D006566:Herpesviridae Infections / Q000201:enzymology* / Q000235:genetics / Q000821:virology*; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000502:physiology*; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D000076084:Ubiquitin-Specific Peptidase 7; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D000956:Antigens, Viral; D004279:DNA, Viral; D009687:Nuclear Proteins; D014764:Viral Proteins; C109540:latency-associated nuclear antigen; C464569:USP7 protein, human; D043222:Ubiquitin Thiolesterase; D000076084:Ubiquitin-Specific Peptidase 7