VIRAL PROTEINS THAT INHIBIT FAS AND TNFR1 SIGNALING

描述（改编自研究者摘要）：研究者 已经确定并开始描述一系列独特的蛋白质， 在人腺病毒的E3转录单位内编码。 两 这些蛋白质，称为10.4K和14.5K， 抑制由TNFR 1或Fas连接引发的凋亡的异二聚体， 而不是其它凋亡激活剂。 10.4K/14.5K复合体介导的温度为 至少两种不同的封锁功能：它导致表面消失 在一些病毒感染的细胞上结合Fas，从而阻断信号传导 通过Fas;它还抑制Fas和TNFR 1信号在后受体 结合步骤。 最近，他们发现10.4K和14.5K 独立地与来自病毒感染细胞裂解物的Fas共沉淀。 本申请中描述的实验将确定分子量。 这些蛋白质干扰细胞凋亡的机制。 具体 他们将：1）确定在TNFR 1和Fas的已知成员中， 信号复合物，结合到10.4K和14.5K，以及什么样的破坏， 信号复合物作为这种结合的结果而发生; 2）确定 异源二聚体导致表面Fas丢失的机制， 10.4K、14.5K与Fas结合的亚细胞定位; 和3）确定10.4K/14.5K作用于 导致细胞破坏的凋亡机制。

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.