Nitta Takeshi, Chiba Ayako, Yamamoto Naoki, Yamaoka Shoji
Department of Molecular Virology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo, Tokyo 113-8519, Japan.
Cell Signal. 2004 Sep;16(9):1071-81. doi: 10.1016/j.cellsig.2004.03.001.
Latent membrane protein 1 (LMP1) encoded by Epstein-Barr virus (EBV) is a membrane protein that activates multiple signaling pathways and transcription factors, including NF-kappaB. Our recent report demonstrated that expression of LMP1 induced programmed cell death in an NF-kappaB-dependent manner. In this study, we demonstrate that a variant CAO-LMP1 derived from EBV-infected nasopharyngeal carcinoma (NPC) does not induce cell death unlike the prototype B95.8-LMP1, although both types of LMP1 show NF-kappaB activation to a similar extent. Studies with chimeric or mutated proteins identified two amino acids in the transmembrane domain, which are commonly substituted in NPC-derived LMP1 variants, being critical for cell death induction by B95.8-LMP1. Furthermore, we show that the B95.8 transmembrane domain co-operates with NF-kappaB to trigger cell death program. Thus, our results reveal a particular feature of the transmembrane domain of tumor-derived CAO-LMP1 and suggest its possible contribution to the pathogenesis of NPC.
爱泼斯坦-巴尔病毒（EBV）编码的潜伏膜蛋白1（LMP1）是一种膜蛋白，可激活多种信号通路和转录因子，包括核因子κB（NF-κB）。我们最近的报告表明，LMP1的表达以NF-κB依赖的方式诱导程序性细胞死亡。在本研究中，我们证明，与原型B95.8-LMP1不同，源自EBV感染的鼻咽癌（NPC）的变异体CAO-LMP1不会诱导细胞死亡，尽管这两种类型的LMP1在相似程度上均显示NF-κB激活。对嵌合蛋白或突变蛋白的研究确定了跨膜结构域中的两个氨基酸，这两个氨基酸在NPC衍生的LMP1变异体中通常被取代，它们对B95.8-LMP1诱导细胞死亡至关重要。此外，我们表明B95.8跨膜结构域与NF-κB协同作用以触发细胞死亡程序。因此，我们的结果揭示了肿瘤衍生的CAO-LMP1跨膜结构域的一个特殊特征，并提示其可能对NPC发病机制的作用。
