The adenovirus E3/10.4K-14.5K proteins down-modulate the apoptosis receptor Fas/Apo-1 by inducing its internalization
The adenovirus E3/10.4K-14.5K proteins down-modulate the apoptosis receptor Fas/Apo-1 by inducing its internalization
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DOI：
10.1073/pnas.95.17.10072
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发表时间：
1998-08-18
影响因子：
11.1
通讯作者：
Burgert, HG
中科院分区：
文献类型：
--
作者：
Elsing, A;Burgert, HG
腺病毒（Ads）已经进化出多种机制来逃避宿主的免疫反应。几种免疫调节性Ad蛋白在早期转录单元3（E3）中编码。E3/19 K蛋白干扰抗原呈递和T细胞识别，而E3/10.4K、14.5K和14.7K蛋白可以保护细胞免受肿瘤坏死因子α介导的裂解。在这里，我们描述了E3蛋白的额外活性。表达Ad 2的所有E3蛋白的转染子表现出细胞表面上的凋亡受体CD 95（Fas，APO-1）的显著减少。相反，仅表达E3 A区域的细胞具有正常的Fas水平。因此，E3 B蛋白（10.4K，14.5K或14.7K）之一似乎是造成这种效应的原因。为了鉴定所涉及的E3 B产物，每个单独的E3 B ORF被选择性地破坏。对含有突变E3区的稳定细胞系的检查表明，当10.4K或14.5K ORF被破坏时，Fas表达恢复，而14.7K ORF的突变不能挽救Fas表达。细胞表面Fas的丧失伴随着总Fas水平的类似降低。然而，在溶酶体促剂存在下，Fas在内体/溶酶体囊泡中积累，表明10.4K-14.5K诱导Fas内化和降解。在感染过程中也观察到Fas而不是CD 40的下调，因此，Ad感染的细胞被保护免于Fas介导的凋亡。因此，Fas系统参与了Ad的发病机制。
Adenoviruses (Ads) have evolved multiple mechanisms to evade the host immune response. Several of the immunomodulatory Ad proteins are encoded in early transcription unit 3 (E3). The E3/19K protein interferes with antigen presentation and T cell recognition, whereas the E3/10.4K 14.5K, and 14.7K proteins can protect cells from tumor necrosis factor alpha-mediated lysis. Here, we describe an additional activity of E3 proteins. Transfectants expressing all E3 proteins of Ad2 exhibit a profound reduction of the apoptosis receptor CD95 (Fas, APO-1) on the cell surface. In contrast, cells expressing only the E3A region have normal Fas levels. Thus, one of the E3B proteins (10.4K, 14.5K, or 14.7K) seems to be responsible for this effect. To identify the E3B products involved, each individual E3B ORF mas selectively disrupted. Examination of stable cell lines containing the mutated E3 regions showed that Fas expression is restored when either the 10.4K or the 14.5K ORF is disrupted, whereas mutation of the 14.7K ORF does not rescue Fas expression. Loss of Fas on the cell surface is accompanied by a similar decrease of total Fas levels. However, in the presence of lysosomotropic agents Fas accumulates in endosomal/ lysosomal vesicles, indicating that 10.4K-14.5K induce internalization and degradation of Fas. Down-regulation of Fas but not CD40 is also observed during infection and as a consequence, Ad-infected cells are protected from Fas-mediated apoptosis. Thus, the Fas system is implicated in Ad pathogenesis.