Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated notch by targeting the Sel10 protein
Kaposi's sarcoma herpesvirus-encoded latency-associated nuclear antigen stabilizes intracellular activated notch by targeting the Sel10 protein
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DOI：
10.1073/pnas.0703508104
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发表时间：
2007-10-09
影响因子：
11.1
通讯作者：
Robertson, Erle S.
中科院分区：
文献类型：
--
作者：
Lan, Ke;Verma, Subhash C.;Robertson, Erle S.
进化上保守的Notch信号的失调与肿瘤发生高度相关。细胞内激活的Notch（ICN）是与参与细胞周期调节、分化和增殖的许多细胞基因的转录激活相关的原癌基因。ICN的稳定性受到Sel 10介导的泛素-蛋白酶体途径的严格调节。Sel 10可以作为Notch的负调控因子发挥作用，并表现出肿瘤抑制蛋白的活性。这篇文章表明，卡波西肉瘤相关疱疹病毒（KSHV）潜伏相关核抗原（拉娜）直接与Sel 10相互作用，并在KSHV感染的细胞中形成复合物。这导致ICN泛素化和降解的抑制。拉娜的羧基末端与Sel 10的F-box和WD 40结构域相互作用，并与ICN竞争结合Sel 10。ICN水平的升高对于维持KSHV感染的肿瘤细胞的增殖也是至关重要的。这些发现描述了KSHV编码的拉娜蛋白调节由E3连接酶Sel 10的F盒组分介导的ICN泛素化的机制，从而导致病毒感染细胞的增殖。
Deregulation of the evolutionarily conserved Notch signaling is highly correlated with oncogenesis. Intracellular activated Notch (ICN) is a protooncogene linked to the transcription activation of a number of cellular genes involved in cell cycle regulation, differentiation, and proliferation. Stability of ICN is tightly regulated by the Sel10-mediated ubiquitin-proteasome pathway. Sel10 can function as a negative regulator of Notch and exhibits activities of a tumor-suppressor protein. This article shows that the Kaposi's sarcoma-associated herpesvirus (KSHV) latency-associated nuclear antigen (LANA) directly interacts with Sel10 and forms a complex in KSHV-infected cells. This results in suppression of ICN ubiquitination and degradation. The carboxyl terminus of LANA interacts with the F-box and WD40 domains of Sel10 and competes with ICN for binding to Sel10. This elevated level of ICN is also critical for maintaining the enhanced proliferation of KSHV-infected tumor cells. These findings describe a mechanism by which the KSHV-encoded LANA protein regulates ubiquitination of ICN mediated by the F-box component of the E3 ligase Sel10, leading to proliferation of the virus-infected cells.