VIRAL PROTEINS THAT INHIBIT FAS AND TNFR1 SIGNALING

描述(改编自《调查员摘要》)：调查员 已经确定并开始对一系列独特的蛋白质进行表征， 编码在人腺病毒的E3转录单位内。其中两个 这些被称为10.4K和14.5K的蛋白质形成了一层膜 抑制连接TNFR1或Fas引发的细胞凋亡的异源二聚体， 但不包括其他的细胞凋亡激活剂。10.4K/14.5K复合体在 至少有两种不同的封锁功能：它会导致地表消失 一些病毒感染细胞上的相关Fas，从而阻止信号转导 通过Fas；它还抑制受体后的Fas和TNFR1信号 绑定步骤。最近，他们发现10.4K和14.5K 从病毒感染细胞的裂解物中独立地与Fas共沉淀。 本申请中描述的实验将确定分子 这些蛋白质干扰细胞凋亡的机制。特指 他们将：1)确定在已知的TNFR1和Fas成员中， 信号复合体，结合到10.4K和14.5K，以及在 作为这种绑定的结果，出现了信号复杂；2)确定 杂二聚体导致表面Fas丢失的机制和 10.4K、14.5K与Fas相关性的亚细胞定位； 以及3)确定10.4K/14.5K动作对 导致细胞破坏的细胞凋亡机制。

DESCRIPTION (Adapted from the Investigator's abstract): The investigator has identified and begun to characterize a series of unique proteins, encoded within the E3 transcription unit of human adenoviruses. Two of these proteins, called 10.4K and 14.5K, form a membrane associated heterodimer that inhibits apoptosis triggered by ligation of TNFR1 or Fas, but not other apoptotic activators. The 10.4K/14.5K complex mediates at least two different blockade functions: it causes disappearance of surface associated Fas on some virus infected cells, thereby blocking signaling through Fas; and it also inhibits Fas and TNFR1 signaling at a post-receptor binding step. Most recently they have found that both 10.4K and 14.5K independently co-precipitate with Fas from lysates of virus-infected cells. Experiments described in this application will determine the molecular mechanisms by which these proteins interfere with apoptosis. Specifically they will: 1) determine which, among the known members of the TNFR1 and Fas signaling complexes, bind to 10.4K and 14.5K, and what disruption in the signaling complex occurs as a consequence of this binding; 2) determine the mechanism by which the heterodimer causes loss of surface Fas and the subcellular localization of the association between 10.4K, 14.5K, and Fas; and 3) determine the functional outcome of 10.4K/14.5K action on the apoptotic machinery leading to cellular destruction.