Human cytomegalovirus pUL83 targets core histones to inhibit interferon synthesis and promote viral spread

Anasua Deb, Christina Paulus, Michael Martin Nevels

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Tegument protein pUL83 is the most abundant component of human cytomegalovirus (hCMV) particles. The viral protein is predicted to be composed of three domains: a pyrin association domain (PAD), a carboxy-terminal domain (CTD), and an intrinsically disordered linker domain (amino acids 388–479) located between the PAD and CTD. Although pUL83 has been shown to antagonize interferon (IFN) responses, it has not been fully elucidated how the viral protein may contribute to hCMV replication. In this study we demonstrate that pUL83 associates broadly with viral and host chromatin including condensed chromosomes during mitosis. We further show that the linker domain in pUL83 is both required and sufficient for host chromatin targeting, and that this interaction depends on two evolutionary conserved arginine residues (R453 and R455) in the viral protein. Our data indicate that the pUL83 linker domain specifically associates with human core histones (but not linker histones). Furthermore, pUL83 inhibits IFN-beta and IFN-lambda gene induction, but not expression of other cytokine genes, via a mechanism that largely depends on the linker domain including R453/455. Although earlier studies suggested that pUL83 is dispensable for productive hCMV infection in fibroblasts, we find that the viral protein is necessary for efficient plaque formation in these cells, specifically in the presence of IFN. Finally, the pUL83 linker domain including R453/455 contributes significantly to the plaque size in hCMV-infected fibroblasts. Overall, we propose that pUL83 promotes spread of hCMV by selectively inhibiting induction of IFN gene expression via a novel chromatin-based molecular mechanism involving core histones.
Original languageEnglish
JournalAccess Microbiology
Issue number1A
Publication statusPublished - 8 Apr 2019


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