UL49 is an essential subunit of the viral pre-initiation complex that regulates human cytomegalovirus gene transcription
Declan L. Turner,
Svenja Fritzlar,
Sara Sadeghipour,
Adele A. Barugahare,
Brendan E. Russ,
Stephen J. Turner,
Rommel A. Mathias
Affiliations
Declan L. Turner
Infection and Immunity Program, Monash Biomedicine Discovery Institute, and Department of Microbiology, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia
Svenja Fritzlar
Infection and Immunity Program, Monash Biomedicine Discovery Institute, and Department of Microbiology, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia
Sara Sadeghipour
Infection and Immunity Program, Monash Biomedicine Discovery Institute, and Department of Microbiology, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia
Adele A. Barugahare
Infection and Immunity Program, Monash Biomedicine Discovery Institute, and Department of Microbiology, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia; Monash Bioinformatics Platform, Monash University, Clayton, VIC 3800, Australia
Brendan E. Russ
Infection and Immunity Program, Monash Biomedicine Discovery Institute, and Department of Microbiology, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia
Stephen J. Turner
Infection and Immunity Program, Monash Biomedicine Discovery Institute, and Department of Microbiology, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia
Rommel A. Mathias
Infection and Immunity Program, Monash Biomedicine Discovery Institute, and Department of Microbiology, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia; Department of Biochemistry and Molecular Biology, Monash University, 23 Innovation Walk, Clayton, VIC 3800, Australia; Corresponding author
Summary: More than half the world’s population is infected with human cytomegalovirus (HCMV), causing congenital birth defects and impacting the immuno-compromised. Many of the >170 HCMV genes remain uncharacterized, and this gap in knowledge limits the development of novel antivirals. In this study, we investigated the essential viral protein UL49 and found it displayed leaky late expression kinetics, and localized to nuclear replication compartments. Cells infected with mutant UL49 virus were unable to produce infectious virions and phenocopied other beta-gamma viral pre-initiation complex (vPIC) subunit (UL79, UL87, UL91, UL92, and UL95) mutant infections. RNA-seq analysis of vPIC mutant infections revealed a consistent diminution of genes encoding capsid subunits, including TRX2/UL85 and MCP/UL86, envelope glycoproteins gM, gL and gO, and egress-associated tegument proteins UL99 and UL103. Therefore, as a member of the vPIC, UL49 serves as a fundamental HCMV effector that governs viral gene transcription required to complete the replication cycle.
