Abstract
Herpes simplex virus (HSV-1) lytic infection results in global changes to the host cell proteome and the proteins associated with host chromatin. We present a system level characterization of proteome dynamics during infection by performing a multi-dimensional analysis during HSV-1 lytic infection of human foreskin fibroblast (HFF) cells. Our study includes identification and quantification of the host and viral proteomes, phosphoproteomes, chromatin bound proteomes and post-translational modifications (PTMs) on cellular histones during infection. We analyzed proteomes across six time points of virus infection (0, 3, 6, 9, 12 and 15 h post-infection) and clustered trends in abundance using fuzzy c-means. Globally, we accurately quantified more than 4000 proteins, 200 differently modified histone peptides and 9000 phosphorylation sites on cellular proteins. In addition, we identified 67 viral proteins and quantified 571 phosphorylation events (465 with high confidence site localization) on viral proteins, which is currently the most comprehensive map of HSV-1 phosphoproteome. We investigated chromatin bound proteins by proteomic analysis of the high-salt chromatin fraction and identified 510 proteins that were significantly different in abundance during infection. We found 53 histone marks significantly regulated during virus infection, including a steady increase of histone H3 acetylation (H3K9ac and H3K14ac). Our data provide a resource of unprecedented depth for human and viral proteome dynamics during infection. Collectively, our results indicate that the proteome composition of the chromatin of HFF cells is highly affected during HSV-1 infection, and that phosphorylation events are abundant on viral proteins. We propose that our epi-proteomics approach will prove to be important in the characterization of other model infectious systems that involve changes to chromatin composition.
Highlights
Been shown to induce CBX5/HP1 dissociation from lamin B receptor (LBR) resulting in destabilization of the nuclear envelope
Previous studies suggested that viral US3 kinase may affect the lamin A/C (LMNA) disrupting function of the envelopment apparatus by UL31 phosphorylation [59]
The trends of US3 and UL31 expression patterns and identified UL31 phosphosites (S24, S26, S27) followed the trend of LMNA protein. This may support the significance of S24, S26, S27 sites in the regulation of UL31 localization and function
Summary
Been shown to induce CBX5/HP1 dissociation from LBR resulting in destabilization of the nuclear envelope. Our study presents a combinatorial approach that confirms the existing data that HSV-1 disrupts the nuclear envelope likely through interrupting H3K9me3-based heterochromatin and lamin association of CBX proteins. Phosphorylation of lamin proteins and associated disruption of the lamina is a conserved feature of herpesvirus infection [16, 101,102,103,104,105,106].
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