Proteomics Analysis of Herpes Simplex Virus Type 1-Infected Cells Reveals Dynamic Changes of Viral Protein Expression, Ubiquitylation, and Phosphorylation

Bell, Christina; Desjardins, Michel; Thibault, Pierre; Radtke, Kerstin

doi:10.1021/pr301157j

Cited by 36 publications

(47 citation statements)

References 54 publications

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“…Association with membranes is notoriously challenging for MS because of hydrophobicity and limited proteolytic peptides. For comparison, Bell et al also reported the identification of 67 HSV-1 proteins with similar difficulties detecting UL11, UL20, UL49.5, and US5 proteins (18). Overall, our analysis detected ϳ92% of all expected HSV-1 proteins, confirming accurate representation of the viral proteome in our dataset.…”

Section: Fig 1 Proteome Characterization During Hsv-1 Infection By supporting

confidence: 79%

“…3G). This prior report also found ICP4 (15 sites) as the most heavily phosphorylated viral protein (18). Interestingly, the overall increase in abundance of phosphorylation events on viral proteins appeared delayed as compared with the respective proteome level (supplemental Fig.…”

Section: Phosphoproteomics Analysis Of Host and Viral Proteome Duringsupporting

confidence: 57%

“…S6; supplemental Table S3B). For clustering of the phosphorylation sites on viral proteins we included only those which (18). Confidence -is the confidence score for site localization of the phosphorylation (100% means fully unambiguous).…”

Section: Phosphoproteomics Analysis Of Host and Viral Proteome Duringmentioning

confidence: 99%

“…S7; Table S4B). To our knowledge, only 100 of the 571 identified viral potential phosphorylated residues have been previously described (18,81) (see supplemental Table S4A and associated references).…”

Section: Phosphoproteomics Analysis Of Host and Viral Proteome Duringmentioning

confidence: 99%

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Time-resolved Global and Chromatin Proteomics during Herpes Simplex Virus Type 1 (HSV-1) Infection

Kulej

Avgousti

Sidoli

et al. 2017

Molecular & Cellular Proteomics

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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. Molecular & Cellular Proteomics 16: 10.1074/mcp.M116.065987, S92-S107, 2017. Herpes simplex virus (HSV-1)1 leads to a contagious and persistent infection that affects about 95% of the human population. The HSV-1 genome is a double-stranded DNA molecule that replicates in the host cell nucleus (1). HSV-1 initially infects epithelial cells as a lytic infection, and then enters peripheral neurons where it establishes latency (2, 3). Processes such as viral transcription, viral DNA synthesis, virion assembly and DNA packaging take place in discrete virus-induced structures within the nucleus called replication compartments (1, 4). These processes are temporally regulated by the viral cascades of immediate-early (IE), early (E), and late (L) gene expression. The IE proteins are primarily responsible for counteracting intrinsic host defenses and for activating expression of early-phase genes (1). Early viral pro-

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Section: Fig 1 Proteome Characterization During Hsv-1 Infection By supporting

confidence: 79%

Section: Phosphoproteomics Analysis Of Host and Viral Proteome Duringsupporting

confidence: 57%

Section: Phosphoproteomics Analysis Of Host and Viral Proteome Duringmentioning

confidence: 99%

Section: Phosphoproteomics Analysis Of Host and Viral Proteome Duringmentioning

confidence: 99%

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Time-resolved Global and Chromatin Proteomics during Herpes Simplex Virus Type 1 (HSV-1) Infection

Kulej

Avgousti

Sidoli

et al. 2017

Molecular & Cellular Proteomics

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“…To confirm the specificity of the role of phosphorylation of vdUTPase Ser-187 in viral pathogenesis and replication in mice, we constructed recombinant viruses YK755 (ICP22S5A/S22A/T162A/S167A) and YK757 (UL51T190A), in which the phosphorylation sites in ICP22 and UL51 identified by phosphoproteomic analyses in previous studies (17,43) were replaced with alanines, and their repaired viruses YK756 (ICP22S5A/ S22A/T162A/S167A-repair) and YK758 (UL51T190A-repair) (Fig. 1), and used them to infect cultured cells and mice.…”

Section: Effect Of Phosphorylation Of Vdutpase Ser-187 On Viral Replimentioning

confidence: 98%

Phosphorylation of a Herpes Simplex Virus 1 dUTPase by a Viral Protein Kinase, Us3, Dictates Viral Pathogenicity in the Central Nervous System but Not at the Periphery

Shindo

Maruzuru

Kawaguchi

2014

J Virol

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Herpes simplex virus 1 (HSV-1) encodes Us3 protein kinase, which is critical for viral pathogenicity in both mouse peripheral sites (e.g., eyes and vaginas) and in the central nervous systems (CNS) of mice after intracranial and peripheral inoculations, respectively. Whereas some Us3 substrates involved in Us3 pathogenicity in peripheral sites have been reported, those involved in Us3 pathogenicity in the CNS remain to be identified. We recently reported that Us3 phosphorylated HSV-1 dUTPase (vdUTPase) at serine 187 (Ser-187) in infected cells, and this phosphorylation promoted viral replication by regulating optimal enzymatic activity of vdUTPase. In the present study, we show that the replacement of vdUTPase Ser-187 by alanine (S187A) significantly reduced viral replication and virulence in the CNS of mice following intracranial inoculation and that the phosphomimetic substitution at vdUTPase Ser-187 in part restored the wild-type viral replication and virulence. Interestingly, the S187A mutation in vdUTPase had no effect on viral replication and pathogenic effects in the eyes and vaginas of mice after ocular and vaginal inoculation, respectively. Similarly, the enzyme-dead mutation in vdUTPase significantly reduced viral replication and virulence in the CNS of mice after intracranial inoculation, whereas the mutation had no effect on viral replication and pathogenic effects in the eyes and vaginas of mice after ocular and vaginal inoculation, respectively. These observations suggested that vdUTPase was one of the Us3 substrates responsible for Us3 pathogenicity in the CNS and that the CNS-specific virulence of HSV-1 involved strict regulation of vdUTPase activity by Us3 phosphorylation. IMPORTANCEHerpes simplex virus 1 (HSV-1) encodes a viral protein kinase Us3 which is critical for pathogenicity both in peripheral sites and in the central nervous systems (CNS) of mice following peripheral and intracranial inoculations, respectively. Whereas some Us3 substrates involved in Us3 pathogenicity in peripheral sites have been reported, those involved in Us3 pathogenicity in the CNS remain to be identified. Here, we report that Us3 phosphorylation of viral dUTPase (vdUTPase) at serine 187 (Ser-187), which has been shown to promote the vdUTPase activity, appears to be critical for viral virulence in the CNS but not for pathogenic effects in peripheral sites. Since HSV proteins critical for viral virulence in the CNS are, in almost all cases, also involved in viral pathogenicity at peripheral sites, this phosphorylation event is a unique report of a specific mechanism involved in HSV-1 virulence in the CNS.

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Quantitative proteomic analyses in blood: A window to human health and disease

Whittaker

Burgess

Jones

et al. 2019

Journal of Leukocyte Biology

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This review discusses how the measurement of proteins in blood and its components via quantitative proteomics analyses can inform health status. Various external and internal factors such as environmental conditions, genetic background, nutrition, diet, and lifestyle, chronic pathological conditions, disease state, or therapeutic intervention will be investigated and their effects on the protein profile will be shown. The resulting changes to ones’ health and how this protein expression information can be used in early screening/diagnostic applications, drug discovery, precision treatment, patient management, and monitoring overall health status will also be presented.

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Proteomics Analysis of Herpes Simplex Virus Type 1-Infected Cells Reveals Dynamic Changes of Viral Protein Expression, Ubiquitylation, and Phosphorylation

Cited by 36 publications

References 54 publications

Time-resolved Global and Chromatin Proteomics during Herpes Simplex Virus Type 1 (HSV-1) Infection

Time-resolved Global and Chromatin Proteomics during Herpes Simplex Virus Type 1 (HSV-1) Infection

Phosphorylation of a Herpes Simplex Virus 1 dUTPase by a Viral Protein Kinase, Us3, Dictates Viral Pathogenicity in the Central Nervous System but Not at the Periphery

Quantitative proteomic analyses in blood: A window to human health and disease

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