EC5S ubiquitin complex is recruited by KSHV latent antigen LANA for degradation of the VHL and p53 tumor suppressors.
EC5S ubiquitin complex is recruited by KSHV latent antigen LANA for degradation of the VHL and p53 tumor suppressors.
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DOI：
10.1371/journal.ppat.0020116
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发表时间：
2006-10
期刊：
影响因子：
6.7
通讯作者：
Robertson, Erle S
中科院分区：
文献类型：
--
作者：
Cai, Qi-Liang;Knight, Jason S;Verma, Suhbash C;Zald, Philip;Robertson, Erle S
病毒可以利用细胞蛋白质降解途径来建立有利于其繁殖的环境。在这里，我们报告的卡波西肉瘤相关疱疹病毒（KSHV）编码的潜伏相关核抗原（拉娜）直接作为一个组件的EC 5S泛素复合物靶向肿瘤抑制因子von Hippel-Lindau（VHL）和p53的降解。我们已经确定了拉娜中的细胞因子信号传导抑制盒样基序，其由Elongin B和C盒以及Cullin盒组成，Cullin盒在空间上位于其氨基和羧基末端。该基序是拉娜与Cul 5-Elongin BC复合物相互作用所必需的，以分别通过其氨基末端和羧基末端结合结构域促进细胞底物VHL和p53在体外的多泛素化。在转染的细胞以及KSHV感染的B淋巴瘤细胞中，拉娜表达刺激VHL和p53的降解。此外，特异性RNA干扰介导的拉娜敲低稳定了原发性渗出性淋巴瘤细胞中的VHL和p53。因此，通过拉娜操纵肿瘤抑制因子可能为KSHV感染的肿瘤细胞的进展提供有利的环境。泛素是一种分子量为8.5kDa的小分子多肽，由76个氨基酸组成，在真核生物中高度保守。细胞蛋白质降解的目的是共价连接到泛素的过程称为泛素化。这种高度调节的过程控制着广泛的基本细胞功能，包括信号转导、发育和凋亡。许多病原体通过模仿、阻断或重定向细胞泛素系统的活性来侵入宿主细胞。了解这些病原体针对的独特生物学功能是制定预防和保护其入侵策略的关键目标。本报告描述了一个独特的功能作用的潜伏相关核抗原（拉娜）编码的卡波西肉瘤相关疱疹病毒，一个大的DNA病毒，持续存在于原发性渗出性淋巴瘤和多中心Castleman病。拉娜可以通过下调B淋巴瘤细胞中关键的肿瘤抑制因子von Hippel-Lindau（VHL）和p53来调节缺氧诱导因子1α的活性。在该途径中，拉娜通过非常规蛋白基序直接模拟并充当特异性E3泛素复合物的接头分子，以刺激VHL和p53的泛素化和降解。这是至关重要的，因为它提出了一个有趣的问题，即这个过程是否与人类癌症相关的肿瘤病毒的感染和发病机制有关。
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. Ubiquitin is a small 8.5-kDa polypeptide with 76 amino acids which is highly conserved in eukaryotes. Cellular proteins destined for degradation are covalently linked to ubiquitin by a process called ubiquitylation. This highly regulated process controls a broad range of fundamental cellular functions, including signal transduction, development, and apoptosis. Many pathogens invade host cells by mimicking, blocking, or redirecting the activity of the cellular ubiquitin system. Understanding the unique biological functions targeted by these pathogens is a key goal in developing strategies for prevention and protection against their invasions. This report describes a unique functional role of the latency-associated nuclear antigen (LANA) encoded by Kaposi's sarcoma–associated herpesvirus, a large DNA virus that persists in primary effusion lymphoma and multicentric Castleman's disease. LANA can modulate hypoxia-inducible factor 1α activities by down-regulation of the critical tumor suppressors von Hippel-Lindau (VHL) and p53 in B lymphoma cells. In this pathway, LANA directly mimics and serves as an adaptor molecule for a specific E3 ubiquitin complex through an unconventional protein motif, to stimulate the ubiquitylation and degradation of both VHL and p53. This is of fundamental importance because it raises the interesting question as to whether this process is linked to regulation of infection and pathogenesis by tumor viruses associated with human cancers.