Inhibition of Programmed Cell Death by Cytomegalovirus

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Programmed cell death (PCD) plays an important role as an innate immune defense against viral infections. In previous work we have shown that murine cytomegalovirus (MCMV) encodes at least four cell death inhibitors: The M36 protein inhibits death receptor-mediated apoptosis by blocking caspase-8 activation. More recently, we have shown that the MCMV M45 protein binds to the cellular adapter protein RIP1 and blocks RIPl-meditated PCD and the activation of NF-KB and p38 MAP kinase. M45 s function as an inhibitor of RIP1- mediated signalling (vIRS) represents a novel mechanism of viral interference with the cellular stress response. Recently published data suggest that MCMV encodes several mitochondrial proteins, which could participate in the inhibition of PCD at the mitochondrial checkpoint. We have shown that the MCMV m38.5 protein specifically blocks BAX-mediated cell death, and preliminary data from our laboratory indicate that a viral small mitochondrial protein (vSMP) is responsible for inhibiting BAK. In the proposed project we want to analyze the functional properties of the viral proteins vIRS and vSMP as well as possible homologs of these proteins in human cytomegalovirus.