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

被引:157
作者
Cai, Qi-Liang
Knight, Jason S.
Verma, Suhbash C.
Zald, Philip
Robertson, Erle S. [1 ]
机构
[1] Univ Penn, Sch Med, Abramson Comprehens Canc Ctr, Dept Microbiol, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Abramson Comprehens Canc Ctr, Tumor Virol Program, Philadelphia, PA 19104 USA
关键词
D O I
10.1371/journal.ppat.0020116
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
引用
收藏
页码:1002 / 1012
页数:11
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