Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors
Bcl-xL inhibits T-cell apoptosis induced by expression of SARS coronavirus E protein in the absence of growth factors
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DOI：
10.1042/bj20050698
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发表时间：
2005-11-15
影响因子：
4.1
通讯作者：
Yang, XF
中科院分区：
文献类型：
--
作者：
Yang, Y;Xiong, ZY;Yang, XF
严重急性呼吸综合征(SARS)患者的标志性发现之一是淋巴细胞减少，这是大量淋巴细胞死亡的结果。SARS冠状病毒(SARS-CoV，SARS-CoV)是与小鼠肝炎冠状病毒(MHV，MHV)同源的一种新的冠状病毒，具有诱导细胞凋亡的功能。我们推测SARS-CoV编码一个与MHV E蛋白同源的小包膜E蛋白，从而诱导T细胞凋亡。为了验证这一假设，我们利用全基因合成技术合成了编码SARS-CoVE蛋白的基因。我们的结果表明，SARS-CoV E蛋白诱导了转基因Jurkat T细胞的凋亡，在没有生长因子的情况下，这种凋亡被放大到更高的凋亡率。而过表达的抗凋亡蛋白Bclxl可抑制细胞的凋亡。此外，我们还发现SARS-CoV E蛋白在体外与BclxL相互作用，在体内与内源性BclxL相互作用，BclxL与SARS-CoVE蛋白的相互作用是由BH3(Bcl2同源域3)介导的。最后，我们在SARS-CoV E蛋白的C末端胞浆结构域中发现了一个新的BH3样区，它介导了其与Bclxl的结合。这些结果首次证明了一种新的T细胞凋亡的分子机制，这种机制有助于在大多数SARS患者中观察到SARS-CoV诱导的淋巴细胞减少。
One of the hallmark findings in patients suffering from SARS (severe acute respiratory syndrome) is lymphopenia, which is the result of massive lymphocyte death. SARS-CoV (SARS coronavirus), a novel coronavirus that has been etiologically associated with SARS cases, is homologous with MHV (murine hepatitis coronavirus), and MHV small envelope E protein is capable of inducing apoptosis. We hypothesized that SARS-CoV encodes a small envelope E protein that is homologous with MHV E protein, thus inducing T-cell apoptosis. To test this hypothesis, a cDNA encoding SARS-CoV E protein was created using whole gene synthesis. Our results showed that SARS-CoV E protein induced apoptosis in the transfected Jurkat T-cells, which was amplified to higher apoptosis rates in the absence of growth factors. However, apoptosis was inhibited by overexpressed antiapoptotic protein Bcl-xL. Moreover, we found that SARS-CoV E protein interacted with Bcl-xL in vitro and endogenous Bcl-xL in vivo and that BclxL interaction with SARS-CoV E protein was mediated by BH3 (Bcl-2 homology domain 3) of Bcl-xL. Finally, we identified a novel BH3-like region located in the C-terminal cytosolic domain of SARS-CoV E protein, which mediates its binding to Bcl-xL. These results demonstrate, for the first time, a novel molecular mechanism of T-cell apoptosis that contributes to the SARS-CoV-induced lymphopenia observed in most SARS patients.