The human cytomegalovirus (HCMV) tegument protein UL69 is important for efficient viral replication at low multiplicities of infection. Several molecular mechanisms by which UL69 contributes to HCMV replication have been proposed, including UL69's ability to interact with the mRNA export factors UAP56 and URH49 to facilitate the shuttling of viral mRNAs from the nuclei of infected cells. Using a UL69 viral mutant that is unable to bind UAP56 and URH49, we demonstrated that UL69's interaction with UAP56 or URH49 does not contribute to the growth phenotype associated with the UL69 deletion mutant.Human cytomegalovirus (HCMV) encodes roughly 25 proteins that compose the tegument layer, which resides between the nucleocapsid and the viral envelope. These proteins are packaged within the mature virion, are delivered to the host cell immediately upon infection, and play important roles in entry, gene regulation, immune evasion, DNA replication, virion assembly, and viral egress (8, 9). The UL69 tegument protein has previously been shown to play an important role in regulating efficient replication of HCMV (5). Infection with a UL69 deletion mutant results in a severely multiplicity-dependent growth phenotype (5). However, the mechanism whereby UL69 contributes to viral replication has remained elusive. Previous studies have provided clues as to how UL69 may participate in regulating HCMV replication. Activities associated with UL69 include its ability to regulate cell cycle progression (5, 13), regulate viral gene expression (5), shuttle between the nucleus and cytoplasm (10, 12), bind RNA (19), and interact with itself (11) and several cellular proteins (1,12,16,18,21).UL69 and its herpesvirus homologues are thought to function in part by regulating the export of intronless viral mRNAs from the nucleus to the cytoplasm within infected cells (10,12,20). In support of this, UL69 has been shown to interact with the cellular factors U2AF65-associated protein 56 (UAP56) and the 90% identical UAP56-related helicase 49 (URH49) (12). UAP56 and URH49 are DEAD-box helicases, which are RNA-dependent ATPases that play important roles in connecting pre-mRNA splicing with mature mRNA export (14, 15). The ability of UL69 to bind UAP56 and/or URH49 has been hypothesized to be critical for its ability to promote the export of viral transcripts during infection and to play a critical role in controlling viral replication (12,20). Even though previous studies have clearly demonstrated that UL69 can bind to UAP56 and URH49 and that these interactions are required for the efficient nuclear export of an unspliced reporter gene, the significance of UL69's interaction with UAP56 and/or URH49 has not been determined in the context of a productive viral infection where these proteins are expressed at physiological levels and in the presence of the full complement of viral proteins. Therefore, this study utilizes a UL69 UAP56/ URH49 viral binding mutant to determine if UL69's interaction with UAP56 or URH49 is required for efficient HCMV repli...
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