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

Abstract

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.Nuclear domains 10 (ND10), also called PML nuclear bodies or PML oncogenic domains (PODs), represent intranuclear accumulations of several proteins, including the transcription repressors PML, Sp100, HP1, and Daxx. Within the highly specialized intranuclear architecture, ND10 presumably act as nuclear depots to maintain the homeostatic balance through controlled recruitment and release of proteins (reviewed in references 24 and 27). PML is the key component for ND10 maintenance and is responsible for the recruitment of other proteins to ND10. Daxx is recruited to ND10 from condensed chromatin through interaction with PML modified by a small ubiquitin-like modifier (SUMO-1) (15). Human Daxx was originally discovered as a DNA-binding protein (17) and has been reported to be involved in several cellular processes, including apoptosis, transcription regulation, and embryo development (reviewed in reference 26). The growing list of Daxx-interacting partners suggests that Daxx acts as a protein modulator in numerous cellular activities, while its accumulation at ND10 appears to regulate the availability of soluble Daxx for these processes.At least three ND10 proteins, PML, Sp100, and Daxx, are upregulated by interferon (7,9,10,33), suggesting the potential involvement of ND10 in the antiviral cellular response. Indeed, studies have demonstrated that several DNA viruses start their synthetic processes in the immediate vicinity of ND10 (reviewed in reference 23). Input viral DNA accumulates at ND10, followed by transcription and replication juxtaposed to ND10. The structure of ND10 becomes modified in a virus-specific manner through the action of immediate-early (IE) proteins. Thus, human cytomegalovirus (HCMV) forms a highly dynamic immediate transcript environment (ITE) during the IE stage of infection as it begins transcription juxtaposed to ND10 (16). The HCMV IE1 protein accumulates at ND10 and eventually disperses the structure (1, 18, 34), possibly through direct interaction with PML (1), while the IE2 protein accumulates juxtaposed to a subpopulation of ND10 where HCMV starts transcription, thus providing an ITE marker (16). This high spatial-temporal correlation suggests that ND10 functionally influence viral infection, although the reasons for this relationship and the consequences for virus and cell remain unclear. To further understand the early association between ND10 and viruses, we examined the processes that occur before the initiation of viral transcription, focusing on the association of HCMV tegument transactivators with ND10.During infection, the viral envelope fuses with the cell membrane, delivering tegument proteins located between the membrane envelope an...

Establishment of papillomavirus infection is enhanced by promyelocytic leukemia protein (PML) expression

“…7 and 8), but a role for ND10 in their transcription has not been fully established. For example, although parental human cytomegalovirus and simian virus 40 genomes are found in association with ND10 (35)(36)(37), the levels of viral RNA were unaltered in cells lacking PML and ND10 (37,38), in contrast to our findings for PV.…”

“…Capsid proteins have not previously been implicated in the deposition of a viral genome at ND10. The example of the human cytomegalovirus (HCMV) tegument protein, pp71, which functions to activate viral immediate early transcription (43) and has been shown to be necessary for genome localization and transcription at ND10 (35), may have some similarities, but, as previously mentioned, the absence of ND10 does not affect the level of HCMV transcripts (38). L2 is not known to possess any transcriptional activity, which suggests that its main function in this process is to localize the DNA to a site that favors transcription.…”

Nuclear Aggresomes Form by Fusion of PML-associated Aggregates

“…This hypothesis is supported by the alterations in PML bodies described during DNA and RNA virus infections (reviewed in Doucas and Evans, 1996). In cells infected with Hepatitis delta virus , herpes simplex virus-1, human cytomegalovirus (Ishov et al, 2002), or human papilloma virus (Becker et al, 2004), the virus localizes to enlarged PMLs, and in some cases subsequently disrupts PML bodies (Everett and Maul, 1994). It should be stressed that viruses are highly ordered protein aggregates.…”

Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts

“…Our data further demonstrate that the nuclear release of DAXX increases its association with FADD, which may serve as an explanation for the proapoptotic effects of SENP1. The question of whether this is the only mechanism by which DAXX exerts its effects in RA SFs, however, remains to be answered, because it has been shown that DAXX may also function as an adaptor molecule that recruits other proteins to PML NBs (24) and more recent data have demonstrated a role for DAXX as a transcriptional repressor of key transcriptional factors. In this context, the observation that DAXX interacts with Smad4 and represses its transcriptional activity (25) as well as data showing that the interaction of SUMO-1-modified CREB-binding protein (CBP) with DAXX mediates SUMO-dependent transcriptional regulation of CBP (26) are certainly of importance.…”