Daxx-Mediated Accumulation of Human Cytomegalovirus Tegument Protein pp71 at ND10 Facilitates Initiation of Viral Infection at These Nuclear Domains

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Abstract
Human cytomegalovirus (HCMV) starts immediate-early transcription at nuclear domains 10 (ND10), forming a highly dynamic immediate transcript environment at this nuclear site. The reason for this spatial correlation remains enigmatic, and the mechanism for induction of transcription at ND10 is unknown. We investigated whether tegument-based transactivators are involved in the specific intranuclear location of HCMV. Here, we demonstrate that the HCMV transactivator tegument protein pp71 accumulates at ND10 before the production of immediate-early proteins. Intracellular trafficking of pp71 is facilitated through binding to a coiled-coil region of Daxx. The C-terminal domain of Daxx then interacts with SUMO-modified PML, resulting in the deposition of pp71 at ND10. In Daxx-deficient cells, pp71 does not accumulate at ND10, proving in vivo the necessity of Daxx for pp71 deposition. Also, HCMV forms immediate transcript environments at sites other than ND10 in Daxx-deficient cells, and so does the HCMV pp71 knockout mutant UL82−/− in normal cells. This result strongly suggests that pp71 and Daxx are essential for HCMV transcription at ND10. Lack of Daxx had the effect of reducing the infection rate. We conclude that the tegument transactivator pp71 facilitates viral genome deposition and transcription at ND10, possibly priming HCMV for more efficient productive infection.