EC5S ubiquitin complex is recruited by KSHV latent antigen LANA for degradation of the VHL and p53 tumor suppressors

PLoS Pathog. 2006 Oct;2(10):e116. doi: 10.1371/journal.ppat.0020116.

Abstract

Cellular protein degradation pathways can be utilized by viruses to establish an environment that favors their propagation. Here we report that the Kaposi's sarcoma-associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen (LANA) directly functions as a component of the EC5S ubiquitin complex targeting the tumor suppressors von Hippel-Lindau (VHL) and p53 for degradation. We have characterized a suppressor of cytokine signaling box-like motif within LANA composed of an Elongin B and C box and a Cullin box, which is spatially located at its amino and carboxyl termini. This motif is necessary for LANA interaction with the Cul5-Elongin BC complex, to promote polyubiquitylation of cellular substrates VHL and p53 in vitro via its amino- and carboxyl-terminal binding domain, respectively. In transfected cells as well as KSHV-infected B lymphoma cells, LANA expression stimulates degradation of VHL and p53. Additionally, specific RNA interference-mediated LANA knockdown stabilized VHL and p53 in primary effusion lymphoma cells. Thus, manipulation of tumor suppressors by LANA potentially provides a favorable environment for progression of KSHV-infected tumor cells.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Antigens, Viral / genetics
  • Antigens, Viral / metabolism*
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Line
  • Cell Line, Tumor
  • Cullin Proteins / genetics
  • Cullin Proteins / metabolism
  • Elongin
  • Gene Expression Regulation, Viral / genetics
  • Gene Expression Regulation, Viral / physiology
  • Herpesvirus 8, Human / genetics
  • Herpesvirus 8, Human / metabolism
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Molecular Sequence Data
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Binding / genetics
  • Protein Binding / physiology
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Suppressor of Cytokine Signaling Proteins / genetics
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin / genetics
  • Ubiquitin / metabolism*
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism*

Substances

  • Antigens, Viral
  • CUL5 protein, human
  • Carrier Proteins
  • Cullin Proteins
  • ELOB protein, human
  • Elongin
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • RBX1 protein, human
  • Suppressor of Cytokine Signaling Proteins
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Ubiquitin
  • latency-associated nuclear antigen
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein

Associated data

  • GENBANK/BC001466
  • GENBANK/BC013809
  • GENBANK/BC065000
  • GENBANK/U22431
  • GENBANK/U52064
  • RefSeq/NC_003409
  • RefSeq/NM_000546
  • RefSeq/NM_003478
  • RefSeq/NM_003591
  • RefSeq/NM_198156