Snapshots: Chromatin control of viral infection

Knipe, David M.; Lieberman, Paul M.; Jung, Jae U.; McBride, Alison A.; Morris, Kevin V.; Ott, Melanie; Margolis, David M.; Nieto, Amelia; Nevels, Michael; Parks, Robin J.; Kristie, Thomas M.

doi:10.1016/j.virol.2012.09.023

Cited by 143 publications

(148 citation statements)

References 99 publications

(131 reference statements)

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“…Unlike viral RNAs, which are distinct from cellular RNAs and therefore recognized by intracellular PRRs, DNA genomes of viruses that replicate in the nucleus are thought to be chemically and structurally similar to host DNA (2)(3)(4). It was therefore generally accepted that viral DNA sensing was limited to the cytoplasm where aberrant DNA accumulation would be perceived as "foreign."…”

Section: Virus-host Interactionsmentioning

confidence: 99%

cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection

Orzalli

Broekema

Diner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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212

225

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Interferon γ-inducible protein 16 (IFI16) and cGMP-AMP synthase (cGAS) have both been proposed to detect herpesviral DNA directly in herpes simplex virus (HSV)-infected cells and initiate interferon regulatory factor-3 signaling, but it has been unclear how two DNA sensors could both be required for this response. We therefore investigated their relative roles in human foreskin fibroblasts (HFFs) infected with HSV or transfected with plasmid DNA. siRNA depletion studies showed that both are required for the production of IFN in infected HFFs. We found that cGAS shows low production of cGMP-AMP in infected cells, but instead cGAS is partially nuclear in normal human fibroblasts and keratinocytes, interacts with IFI16 in fibroblasts, and promotes the stability of IFI16. IFI16 is associated with viral DNA and targets to viral genome complexes, consistent with it interacting directly with viral DNA. Our results demonstrate that IFI16 and cGAS cooperate in a novel way to sense nuclear herpesviral DNA and initiate innate signaling.protein-protein interactions | DNA sensing | innate immunity | virus-host interactions T he innate immune response is a crucial component of host immunity and is the first line of defense against microbial pathogens, including bacteria and viruses. The initial events during infection of a host cell induce intracellular signaling pathways, resulting in the production of proinflammatory cytokines and IFNs. These effector molecules activate an antiviral state in neighboring cells and recruit immune cells to promote clearance of infection. Viral nucleic acids are potent activators of these signaling pathways and are recognized by a subset of host cell pattern recognition receptors (PRRs). These PRRs include the membrane-bound Toll-like receptors, the cytosolic RIG-Ilike receptors, and a broad class of putative DNA sensors, which include both cytosolic and nuclear proteins (1).Unlike viral RNAs, which are distinct from cellular RNAs and therefore recognized by intracellular PRRs, DNA genomes of viruses that replicate in the nucleus are thought to be chemically and structurally similar to host DNA (2-4). It was therefore generally accepted that viral DNA sensing was limited to the cytoplasm where aberrant DNA accumulation would be perceived as "foreign." However, this dogma has recently been challenged by the identification of DNA-sensing pathways that are active in the nucleus. The Pyrin and HIN-containing interferon γ-inducible protein 16 (IFI16) protein, initially described as a cytosolic DNA sensor (5), has been demonstrated to be nuclear in many cells and to promote the activation of inflammasomes (6, 7) and production of IFNs (8, 9) in response to herpesvirus infection. These initial studies involved short-term siRNA depletion of IFI16; in addition, a recent study showed that long-term knockdown of IFI16 expression led to abrogated IFN responses to not only DNA viruses, such as herpes simplex virus (HSV), but also RNA viruses, such as Sendai virus (10).cGMP-AMP synthase (cGAS) was also ident...

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Section: Virus-host Interactionsmentioning

confidence: 99%

cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection

Orzalli

Broekema

Diner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

212

225

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“…However, even though a prior study identified phosphorylation on HSV-1 proteins (18), a global picture of regulation of host phosphorylation upon HSV-1 infection has not been fully investigated. Moreover, virus infection globally affects the host epigenome (19), thus histone PTMs are of particular interest during HSV-1 infection. Histone PTM relative abundance and location is related to chromatin condensation, gene expression, or recruitment of other proteins to chromatin.…”

Section: Herpes Simplex Virus (Hsv-1)mentioning

confidence: 99%

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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“…In neurons, the viruses establish a latent infection (2,3). In the course of latent infection, the genes expressing the viral proteins are repressed (4,5), and only a long noncoding RNA designated as a latency-associated transcript (LAT) (6)(7)(8)(9) and microRNAs are expressed (10)(11)(12). Periodically, in response to physical hormonal or emotional stress, the virus replicates and is transported to a site at or near the portal of entry into the body where it can cause a lesion.…”

mentioning

confidence: 99%

Modulation of reactivation of latent herpes simplex virus 1 in ganglionic organ cultures by p300/CBP and STAT3

Zhou

Roizman

2013

Proc. Natl. Acad. Sci. U.S.A.

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A key property of herpes simplex viruses (HSVs) is their ability to establish latent infection in sensory or autonomic ganglia and to reactivate on physical, hormonal, or emotional stress. In latently infected ganglia, HSV expresses a long noncoding RNA and a set of microRNAs, but viral proteins are not expressed. The mechanism by which latent HSV reactivates is unknown. A key question is, what is the mechanism of reactivation in the absence of tegument proteins that enable gene expression in productive infection? Elsewhere we have reported the use of ganglionic organ cultures that enable rapid reactivation in medium containing antibody to NGF or delayed reactivation in medium containing NGF and EGF. We also reported that in the ganglionic organ cultures incubated in medium containing antibody to NGF, all viral genes are derepressed at once without requiring de novo protein synthesis within the time frame of a single replicative cycle. Here we report that latent HSV in ganglia immersed in medium containing NGF and EGF is reactivated by (i) broad spectrum as well as specific histone deacetylase 1 or histone deacetylase 4 inhibitors, (ii) activation of p300/CBP, and (iii) either STAT3 carrying the substitution of tyrosine 705 to phenylalanine or an inhibitor of STAT3. Conversely, reactivation of latent HSV was blocked by p300/CBP inhibitor in medium containing antibody to NGF. The results suggest that (i) STAT3 is required for the maintenance of the latent state and interference with its functions leads to reactivation and (ii) p300/CBP is essential for HSV reactivation.latency-associated transcript | nerve growth factor

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Snapshots: Chromatin control of viral infection

Cited by 143 publications

References 99 publications

cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection

cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection

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

Modulation of reactivation of latent herpes simplex virus 1 in ganglionic organ cultures by p300/CBP and STAT3

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