Herpes Simplex Virus 1 Infection Activates Poly(ADP-Ribose) Polymerase and Triggers the Degradation of Poly(ADP-Ribose) Glycohydrolase

Grady, Sarah L.; Hwang, Jesse; Vastag, Livia; Rabinowitz, Joshua D.; Shenk, Thomas

doi:10.1128/jvi.00495-12

Cited by 59 publications

(74 citation statements)

References 48 publications

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“…Extracts were dried under nitrogen gas at room temperature, resuspended in water (HPLC grade), and centrifuged at 16,000 × g for 5 min. Metabolites were identified and measured by an Orbitrap mass spectrometer (Thermo Scientific Exactive) (77), and Metabolomic Analysis and Visualization Engine (MAVEN) software was used for the quantitative analysis of metabolite levels (66,78,79). Metabolite identities were determined by exact mass and retention time match to authenticated standards.…”

Section: Methodsmentioning

confidence: 99%

Estrogen-related receptor α is required for efficient human cytomegalovirus replication

Hwang¹,

Purdy

Wu³

et al. 2014

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

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An shRNA-mediated screen of the 48 human nuclear receptor genes identified multiple candidates likely to influence the production of human cytomegalovirus in cultured human fibroblasts, including the estrogen-related receptor α (ERRα), an orphan nuclear receptor. The 50-kDa receptor and a 76-kDa variant were induced posttranscriptionally following infection. Genetic and pharmacological suppression of the receptor reduced viral RNA, protein, and DNA accumulation, as well as the yield of infectious progeny. In addition, RNAs encoding multiple metabolic enzymes, including enzymes sponsoring glycolysis (enolase 1, triosephosphate isomerase 1, and hexokinase 2), were reduced when the function of ERRα was inhibited in infected cells. Consistent with the effect on RNAs, a substantial number of metabolites, which are normally induced by infection, were either not increased or were increased to a reduced extent in the absence of normal ERRα activity. We conclude that ERRα is needed for the efficient production of cytomegalovirus progeny, and we propose that the nuclear receptor contributes importantly to the induction of a metabolic environment that supports optimal cytomegalovirus replication.herpesvirus | metabolism | nuclear receptor | mass spectrometry H uman cytomegalovirus (HCMV) belongs to the β-herpesvirus subfamily, and although most healthy individuals remain asymptomatic subsequent to infection, the pathogen is a major contributor to birth defects and to life-threatening disease in immunocompromised patients (1-3). As with all viruses, HCMV depends on the host cell to provide macromolecular building blocks for virion production, and throughout the course of its evolution, HCMV has adapted to manipulate numerous fundamental cellular processes, including RNA accumulation (4), translation (5), metabolism (6, 7), secretory pathways (8), and the cell cycle (9).The nuclear receptor gene family, of which there are 48 members in the human genome, encodes transcription factors (10). Some bind to specific hydrophobic ligands such as steroids, vitamin D, fatty acids, and lipids, providing a means to sense changes in the extracellular or intracellular environment; others are "orphans" with no known ligand, and are often constitutively active (11). As transcription factors that modulate broad gene regulatory networks, nuclear receptors control numerous physiological processes, including aspects of metabolism (cell autonomously and at the whole-organism level), development, and cellular differentiation, cancer, circadian rhythm, and immunity (11).The first indication that nuclear receptor signaling modulates HCMV replication surfaced after the identification of a retinoic acid response element within the major immediate-early promoter (MIEP) that caused a dose-dependent response to retinoic acid in reporter assays (12). Retinoic acid was further shown to enhance viral DNA replication and progeny production in human embryonal carcinoma cells and foreskin fibroblasts (13,14). The ligand also exacerbated symptoms of infection,...

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Section: Methodsmentioning

confidence: 99%

Estrogen-related receptor α is required for efficient human cytomegalovirus replication

Hwang¹,

Purdy

Wu³

et al. 2014

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

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“…AS1 knockdown cells also appear to have an altered glutathione: glutathione disulfide ratio compared with infected cells, suggesting a change in redox state. It has been shown, however, that the HSV-1-induced metabolic reprogramming is maintained even when redox state is purposefully perturbed (4).…”

Section: Discussionmentioning

confidence: 99%

“…After the 1-h adsorption period, the cells were washed and new serum-free media was applied. At various times after infection, metabolites were quenched and harvested as described (1,4). Briefly, medium was rapidly removed from cells and cold 80% methanol was added to quench any further metabolic processes.…”

Section: Discussionmentioning

confidence: 99%

“…HCMV (strain AD169) was prepared as reported (45). Viral titers were determined by tissue-culture infectious dose 50/mL (TCID 50 /mL) or IU per well (4). Intracellular viral titers were determined by collecting cell pellets, sonicating these pellets in 1 mL of media, and removing cell debris.…”

Section: Discussionmentioning

confidence: 99%

“…It has been well documented that HSV-1 infection triggers large-scale changes to host cell metabolism (1,4), but the role played by individual cellular metabolic enzymes during the viral life cycle is less understood. To identify host metabolic enzymes that modulate the production of infectious progeny, we performed an siRNA screen (7) (Fig.…”

Section: A Subset Of Human Metabolic Enzymes Modulates Hsv-1 Replicatmentioning

confidence: 99%

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Argininosuccinate synthetase 1 depletion produces a metabolic state conducive to herpes simplex virus 1 infection

Grady¹,

Purdy²,

Rabinowitz

et al. 2013

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

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Herpes simplex virus 1 (HSV-1) infection triggers specific metabolic changes in its host cell. To explore the interactions between cellular metabolism and HSV-1 infection, we performed an siRNA screen of cellular metabolic genes, measuring their effect on viral replication. The screen identified multiple enzymes predicted to influence HSV-1 replication, including argininosuccinate synthetase 1 (AS1), which consumes aspartate as part of de novo arginine synthesis. Knockdown of AS1 robustly enhanced viral genome replication and the production of infectious virus. Using high-resolution liquid chromatography-mass spectrometry, we found that the metabolic phenotype induced by knockdown of AS1 in human fibroblasts mimicked multiple aspects of the metabolic program observed during HSV-1 infection, including an increase in multiple nucleotides and their precursors. Together with the observation that AS1 protein and mRNA levels decrease during wild-type infection, this work suggests that reduced AS1 activity is partially responsible for the metabolic program induced by infection.metabolomics | herpesviruses M any viruses, including herpes simplex virus 1 (HSV-1), human cytomegalovirus (HCMV), influenza, Dengue, hepatitis C, and hepatitis E (1-11), have been shown to significantly perturb metabolic homeostasis over the course of infection. HSV-1 is an intriguing case study, because the virus encodes several of its own metabolic enzymes, including a dUTPase, uracil-DNA glycosylase, ribonucleotide reductase, and thymidine kinase (12). Infection of host cells by multiple strains of HSV-1 induces alterations to central carbon metabolism, such as increased flux through upper glycolysis, and the anapleurotic feeding of carbons into the citric acid (TCA) cycle through the activity of pyruvate carboxylase (1). Infection also induces nucleotide synthesis, manifested by the increased flux of carbons through aspartate to nucleotides, as well as the increased pool levels of multiple nucleotides themselves (1).Although the metabolic reprogramming that occurs during HSV-1 infection has been described, the importance of specific host cell metabolic enzymes to infection is relatively unknown. Here we sought to further resolve the relationship between infection and metabolism by screening for cellular metabolic enzymes that modulate the efficiency of viral infection in primary human fibroblasts. The screen identified several dozen enzymes that modulate HSV-1 growth, including argininosuccinate synthetase (AS1), which antagonized viral replication.AS1 acts as a homotetramer to catalyze the synthesis of argininosuccinate from aspartate and citrulline (13,14). The enzyme plays a role in the production of urea in the kidney and liver, but functions primarily as the limiting step in the citrulline-nitric oxide (NO) cycle in other cell types (15). As a constituent of the citrulline-NO cycle, AS1 participates in the de novo production of the nonessential amino acid arginine as well as the soluble factor NO.We found that AS1 knockdown by siRNA in...

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Viewing teratogens through the lens of nicotinamide adenine dinucleotide (NAD+)

Mark

Dunwoodie

2022

Birth Defects Research

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Background Nicotinamide adenine dinucleotide (NAD+) depletion is associated with numerous diseases in humans. Recently it was revealed that genetic blockage of the NAD+ synthesis pathway in humans causes birth defects in multiple organ systems and miscarriage. Additionally, mice with NAD+ deficiency created through dietary restriction of tryptophan and vitamin B3 were shown to have congenital anomalies affecting virtually every organ system along with miscarriage. Perturbations in NAD+/NADH affect mechanisms of teratogenesis presented by Wilson and others, including genetic alterations, altered energy sources, and lack of precursors and substrates needed for biosynthesis. Methods Medical literature was evaluated to demonstrate how perturbations in NAD+/NADH affect mechanisms of teratogenesis. In addition, literature describing several different teratogens of various types (infectious, physical, maternal health factors, drugs) was reviewed showing the impact of these teratogens on NAD+ and NAD+/NADH ratios. Result Many teratogens affect NAD+ by altering its metabolism, decreasing its intracellular availability, or decreasing its production, which in turn is a plausible mechanism for the creation of birth defects. Conclusion Looking at teratogens through the lens of their impact on NAD+ could provide valuable insight into the mechanism by which some teratogens cause birth defects and miscarriage.

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Herpes Simplex Virus 1 Infection Activates Poly(ADP-Ribose) Polymerase and Triggers the Degradation of Poly(ADP-Ribose) Glycohydrolase

Cited by 59 publications

References 48 publications

Estrogen-related receptor α is required for efficient human cytomegalovirus replication

Estrogen-related receptor α is required for efficient human cytomegalovirus replication

Argininosuccinate synthetase 1 depletion produces a metabolic state conducive to herpes simplex virus 1 infection

Viewing teratogens through the lens of nicotinamide adenine dinucleotide (NAD+)

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