Silencing of Human Cytomegalovirus Gene Expression Mediated by Components of PML Nuclear Bodies

Abstract

Promyelocytic leukemia (PML) nuclear bodies (PML-NBs), also referred to as nuclear domain 10 (ND10), have emerged as a cellular subnuclear structure that mediates an intrinsic defense against viral infections via chromatin-based mechanisms. This structure is defined as nuclear protein accumulations consisting of >100 different factors including the major components PML, hDaxx, Sp100, and SUMO. After infection with human cytomegalovirus (HCMV), which is a herpesvirus of major clinical relevance, PML-NBs are able to induce the silencing of viral immediate-early (IE) gene expression. The tegument protein pp71 of HCMV efficiently antagonizes this PML-NB-based repression by inducing the proteasomal degradation of hDaxx thus facilitating the initiation of IE gene expression. Subsequently, the newly synthesized IE1 protein of HCMV disrupts PML-NBs via a deSUMOylation of PML thereby activating lytic replication. By infection of PML as well as hDaxx knockdown cells, we show that both factors contribute to the deposition of repressive chromatin at the major immediate-early promoter of HCMV thus further confirming the epigenetic silencing mechanism. PML-NB proteins were hypothesized to play a role for both lytic replication as well as for the establishment of latency. However, recent evidence using the latency model of THP1 monocytic cells suggested that PML, Sp100, and hDaxx primarily act as cellular restriction factors that affect the efficacy of differentiation-induced reactivation of HCMV from latency.