Host-viral effects of chromatin assembly factor 1 interaction with HCMV IE2

Abstract

Chromatin assembly factor 1 (CAF1) consisting of p150, p60 and p48 is known to assemble histones onto newly synthesized DNA and thus maintain the chromatin structure. Here, we show that CAF1 expression was induced in human cytomegalovirus (HCMV)-infected cells, concomitantly with global chromatin decondensation. This apparent conflict was thought to result, in part, from CAF1 mislocalization to compartments of HCMV DNA synthesis through binding of its largest subunit p150 to viral immediate-early protein 2 (IE2). p150 interaction with p60 and IE2 facilitated HCMV DNA synthesis. The IE2Q548R mutation, previously reported to result in impaired HCMV growth with unknown mechanism, disrupted IE2/p150 and IE2/histones association in our study. Moreover, IE2 interaction with histones partly depends on p150, and the HCMV-induced chromatin decondensation was reduced in cells ectopically expressing the p150 mutant defective in IE2 binding. These results not only indicate that CAF1 was hijacked by IE2 to facilitate the replication of the HCMV genome, suggesting chromatin assembly plays an important role in herpesviral DNA synthesis, but also provide a model of the virus-induced chromatin instability through CAF1.

Characterization of histone post-translational modifications during virus infection using mass spectrometry-based proteomics

“…et al , reported that histone H1.4 phosphorylation at S35, a variant of H1.2, seems to be necessary for maintaining proper mitotic chromatin structure such as chromatin decondensation [49]. Viruses have been shown to increase nuclear size and result in chromatin decondensation [50,51], these effects are consistent with the changes in H1 phosphorylation induced by adenovirus we observe here.…”

Mutation of Glutamine to Arginine at Position 548 of IE2 86 in Human Cytomegalovirus Leads to Decreased Expression of IE2 40, IE2 60, UL83, and UL84 and Increased Transcription of US8-9 and US29-32

“…compared to WT and Rev-Q548R IE2 genome replication ( Fig. 2A), which could possibly be explained by the recent transfection-based evidence that Q548R IE2 86 cannot bind to the chromatin assembly factor 1 protein p150 (16). However, the large increases in viral DNA levels between 24, 72, and 96 h p.i.…”

Human Cytomegalovirus IE2 Both Activates and Represses Initiation and Modulates Elongation in a Context-Dependent Manner

“…This indicates that other variables, such as high levels of transcription or blockage of sites by other proteins or complexes, influence IE2 occupancy. Previous immunofluorescence studies of IE2 in HCMV-infected cells suggested that IE2 predominantly localizes to the viral replication compartment in late infection and is enriched near viral genomes at PML bodies even prior to replication onset ( 37 , 77 , 78 ). This localization was also dependent on the ability of IE2 to bind DNA ( 37 ).…”