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
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Research Support, N.I.H., Extramural
MeSH terms
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Amino Acid Sequence
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Antigens, Viral / genetics
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Antigens, Viral / metabolism*
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Carrier Proteins / genetics
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Carrier Proteins / metabolism
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Cell Line
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Cell Line, Tumor
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Cullin Proteins / genetics
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Cullin Proteins / metabolism
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Elongin
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Gene Expression Regulation, Viral / genetics
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Gene Expression Regulation, Viral / physiology
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Herpesvirus 8, Human / genetics
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Herpesvirus 8, Human / metabolism
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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Molecular Sequence Data
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Protein Binding / genetics
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Protein Binding / physiology
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Signal Transduction / genetics
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Signal Transduction / physiology
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Suppressor of Cytokine Signaling Proteins / genetics
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Suppressor of Cytokine Signaling Proteins / metabolism
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Transcription Factors / genetics
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Transcription Factors / metabolism
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Tumor Suppressor Protein p53 / metabolism*
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Ubiquitin / genetics
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Ubiquitin / metabolism*
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Von Hippel-Lindau Tumor Suppressor Protein / metabolism*
Substances
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Antigens, Viral
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CUL5 protein, human
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Carrier Proteins
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Cullin Proteins
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ELOB protein, human
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Elongin
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Nuclear Proteins
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RBX1 protein, human
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Suppressor of Cytokine Signaling Proteins
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Transcription Factors
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Tumor Suppressor Protein p53
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Ubiquitin
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latency-associated nuclear antigen
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Ubiquitin-Protein Ligases
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Von Hippel-Lindau Tumor Suppressor Protein
Associated data
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GENBANK/BC001466
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GENBANK/BC013809
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GENBANK/BC065000
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GENBANK/U22431
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GENBANK/U52064
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RefSeq/NC_003409
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RefSeq/NM_000546
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RefSeq/NM_003478
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RefSeq/NM_003591
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RefSeq/NM_198156