title: EC5S ubiquitin complex is recruited by KSHV latent antigen LANA for degradation of the VHL and p53 tumor suppressors.
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.
authors.affiliation: Department of Microbiology and the Tumor Virology Program, Abramson Comprehensive Cancer Center, University of Pennsylvania Medical School, Philadelphia, Pennsylvania, USA.
authors.forename: Qi-Liang
authors.initials: QL
authors.lastname: Cai
authors.forename: Jason S
authors.initials: JS
authors.lastname: Knight
authors.forename: Suhbash C
authors.initials: SC
authors.lastname: Verma
authors.forename: Philip
authors.initials: P
authors.lastname: Zald
authors.forename: Erle S
authors.initials: ES
authors.lastname: Robertson
mesh_terms: D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D044842:Cullin Proteins / Q000235:genetics / Q000378:metabolism; D000075065:Elongin; D015967:Gene Expression Regulation, Viral / Q000235:genetics / Q000502:physiology; D019288:Herpesvirus 8, Human / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025801:Ubiquitin / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
chemical_list: D000956:Antigens, Viral; C496871:CUL5 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; C000616396:ELOB protein, human; D000075065:Elongin; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; C479529:RBX1 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53; D025801:Ubiquitin; C109540:latency-associated nuclear antigen; D044767:Ubiquitin-Protein Ligases; D051794:Von Hippel-Lindau Tumor Suppressor Protein