VIRAL PROTEINS THAT INHIBIT FAS AND TNFR1 SIGNALING

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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.