Function of ankyrin repeat proteins in cowpox virus (CPXV)

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Orthopoxvirus (OPV) genomes consist of a highly conserved central portion primarily encoding genes for poxvirus replication, while sequences towards the ends are more variable. Genes found in these regions encode proteins that govern virulence and immune modulation. One group of these variable genes encode for ankyrin repeat proteins (ARPs). ARPs are common in eukaryotic cells and mainly mediate protein-protein interactions. Some of the ARPs in poxviruses also contain an additional Cterminal F-box domain that is commonly linked to proteasomal degradation. Modified vaccinia virus Ankara (MVA) only specifies one ARP that is encoded by gene 186R and is essential for completion of the viral life cycle in mammalian cells. Sequence analysis predicts that CPXV specifies three ARPs that share high sequence similarity, one of which is called BR211 and represents the orthologue of MVA 186R. We hypothesize that the three ARPs BR006, BR211 and BR220 confer transition into the post-replicative phase of CPXV but that each does so in different sets of host cells. We further surmise that the three CPXV ARPs retarget cellular and viral proteins in a fashion that is dependent on certain phases of virus replication. We will test our hypothesis by two specific aims: 1) Cell-type specific complementation of the deletion of all BR211-like ARPs in CPXV or MVA. 2) Identification of BR211-interacting proteins in different phases of CPXV replication.