Journal
PLOS PATHOGENS
Volume 2, Issue 10, Pages 1002-1012Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.ppat.0020116
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Funding
- NCI NIH HHS [CA091792, R01 CA091792, CA072510] Funding Source: Medline
- NIAID NIH HHS [AI067037, R01 AI067037] Funding Source: Medline
- NIDCR NIH HHS [R01 DE014136, R01 DE017338, DE014136, DE17338] Funding Source: Medline
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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.
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