The ubiquitin-specific protease USP7 modulates the replication of Kaposi's sarcoma-associated herpesvirus latent episomal DNA

J Virol. 2012 Jun;86(12):6745-57. doi: 10.1128/JVI.06840-11. Epub 2012 Apr 18.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antigens, Viral / genetics
  • Antigens, Viral / metabolism
  • Cell Line
  • DNA, Viral / genetics*
  • DNA, Viral / metabolism
  • Herpesviridae Infections / enzymology*
  • Herpesviridae Infections / genetics
  • Herpesviridae Infections / virology*
  • Herpesvirus 8, Human / genetics
  • Herpesvirus 8, Human / physiology*
  • Humans
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Protein Binding
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitin-Specific Peptidase 7
  • Viral Proteins / genetics
  • Viral Proteins / metabolism
  • Virus Latency*
  • Virus Replication*


  • Antigens, Viral
  • DNA, Viral
  • Nuclear Proteins
  • Viral Proteins
  • latency-associated nuclear antigen
  • USP7 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Peptidase 7