Elsing A, Burgert H G
Max von Pettenkofer-Institut, Lehrstuhl Virologie, Genzentrum der Ludwig-Maximilians-Universität, Feodor-Lynen-Strasse 25, 81377 Munich, Germany.
Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):10072-7. doi: 10.1073/pnas.95.17.10072.
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 was 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.
腺病毒（Ads）已经进化出多种机制来逃避宿主的免疫反应。几种免疫调节腺病毒蛋白由早期转录单元3（E3）编码。E3/19K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。在此，我们描述了E3蛋白的另一种活性。表达Ad2所有E3蛋白的转染子在细胞表面的凋亡受体CD95（Fas，APO-1）显著减少。相比之下，仅表达E3A区域的细胞Fas水平正常。因此，E3B蛋白之一（10.4K、14.5K或14.7K）似乎是造成这种效应的原因。为了确定涉及的E3B产物，每个单独的E3B开放阅读框被选择性破坏。对含有突变E3区域的稳定细胞系进行检测表明，当10.4K或l4.5K开放阅读框被破坏时，Fas表达得以恢复，而14.7K开放阅读框的突变并不能挽救Fas表达。细胞表面Fas的缺失伴随着总Fas水平的类似下降。然而，在存在溶酶体促渗剂的情况下，Fas在内体/溶酶体小泡中积累，表明10.4K-14.5K诱导Fas的内化和降解。在感染过程中也观察到Fas而非CD40的下调，结果，腺病毒感染的细胞免受Fas介导的凋亡。因此，Fas系统与腺病毒发病机制有关。
