scholarly journals SARS-CoV-2 hijacks folate and one-carbon metabolism for viral replication

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Yuchen Zhang ◽  
Rui Guo ◽  
Sharon H. Kim ◽  
Hardik Shah ◽  
Shuting Zhang ◽  
...  
Keyword(s):  
Viral Replication ◽  
Carbon Metabolism ◽  
De Novo ◽  
Transcriptional Level ◽  
Viral Genomes ◽  
Infected Cells ◽  
One Carbon Metabolism ◽  
Viral Lifecycle ◽  
Host Metabolism ◽  
Intracellular Glucose

AbstractThe recently identified Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic. How this novel beta-coronavirus virus, and coronaviruses more generally, alter cellular metabolism to support massive production of ~30 kB viral genomes and subgenomic viral RNAs remains largely unknown. To gain insights, transcriptional and metabolomic analyses are performed 8 hours after SARS-CoV-2 infection, an early timepoint where the viral lifecycle is completed but prior to overt effects on host cell growth or survival. Here, we show that SARS-CoV-2 remodels host folate and one-carbon metabolism at the post-transcriptional level to support de novo purine synthesis, bypassing viral shutoff of host translation. Intracellular glucose and folate are depleted in SARS-CoV-2-infected cells, and viral replication is exquisitely sensitive to inhibitors of folate and one-carbon metabolism, notably methotrexate. Host metabolism targeted therapy could add to the armamentarium against future coronavirus outbreaks.

Mammalian orthoreovirus reassortment proceeds with little constraint on segment mixing

2021 ◽  
Author(s):  
Megan R. Hockman ◽  
Nathan T. Jacobs ◽  
Bernardo A. Mainou ◽  
Katia Koelle ◽  
Anice C. Lowen
Keyword(s):  
Viral Replication ◽  
Inclusion Body ◽  
Inclusion Bodies ◽  
Cytoplasmic Inclusion ◽  
Genetic Exchange ◽  
Viral Genomes ◽  
Mammalian Orthoreovirus ◽  
Infected Cells ◽  
Viral Lifecycle ◽  
The Impact

Segmentation of viral genomes gives the potential for genetic exchange within co-infected cells. However, for this potential to be realized, co-infecting genomes must mix during the viral lifecycle. The efficiency of reassortment in turn dictates its potential to drive evolution. The opportunity for mixing within co-infected cells may vary greatly across virus families, such that the evolutionary implications of genome segmentation differ as a result of core features of the viral lifecycle. To investigate the relationship between viral replication compartments and genetic exchange, we quantified reassortment in mammalian orthoreovirus (reovirus). Reoviruses carry a 10-segmented, double-stranded RNA genome, which is replicated within proteinaceous structures termed inclusion bodies. We hypothesized that inclusions impose a barrier to reassortment. We quantified reassortment between wild-type ( wt ) and variant ( var ) reoviruses that differ by one nucleotide per segment. Wt/var systems in both T1L and T3D backgrounds revealed frequent reassortment without bias towards particular genotypes. However, reassortment was more efficient in the T3D serotype. Since T1L and T3D viruses exhibit different inclusion body morphologies, we tested the impact of this phenotype on reassortment. In both serotypes, reassortment levels did not differ by inclusion morphology. Reasoning that the merging of viral inclusions may be critical for genome mixing, we then tested the effect of blocking merging. Reassortment proceeded efficiently even under these conditions. Our findings indicate that reovirus reassortment is highly efficient despite the localization of many viral processes to inclusion bodies, and that the robustness of this genetic exchange is independent of inclusion body structure and fusion. Importance Quantification of reassortment in diverse viral systems is critical to elucidate the implications of genome segmentation for viral evolution. In principle, genome segmentation offers a facile means of genetic exchange between coinfecting viruses. In practice, there may be physical barriers within the cell that limit mixing of viral genomes. Here, we tested the hypothesis that localization of the various stages of the mammalian orthoreovirus lifecycle within cytoplasmic inclusion bodies compartmentalizes viral replication and limits genetic exchange. Contrary to this hypothesis, our data indicate that reovirus reassortment occurs readily within co-infected cells and is not strongly affected by the structure or dynamics of viral inclusion bodies. We conclude that the potential for reassortment to contribute to reovirus evolution is high.

scholarly journals One-Carbon Metabolism in Fatty Liver Disease and Fibrosis: One-Carbon to Rule Them All

2020 ◽  
Vol 150 (5) ◽  
pp. 994-1003
Author(s):  
Robin P da Silva ◽  
Brandon J Eudy ◽  
Rafael Deminice
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Carbon Metabolism ◽  
Fatty Liver Disease ◽  
De Novo ◽  
Future Research ◽  
Excessive Alcohol Consumption ◽  
Nonalcoholic Fatty Liver ◽  
Hepatic Lipid ◽  
One Carbon Metabolism

ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a term used to characterize a range of disease states that involve the accumulation of fat in the liver but are not associated with excessive alcohol consumption. NAFLD is a prevalent disease that can progress to organ damage like liver cirrhosis and hepatocellular carcinoma. Many animal models have demonstrated that one-carbon metabolism is strongly associated with NAFLD. Phosphatidylcholine is an important phospholipid that affects hepatic lipid homeostasis and de novo synthesis of this phospholipid is associated with NAFLD. However, one-carbon metabolism serves to support all cellular methylation reactions and catabolism of methionine, serine, glycine, choline, betaine, tryptophan, and histidine. Several different pathways within one-carbon metabolism that play important roles in regulating energy metabolism and immune function have received less attention in the study of fatty liver disease and fibrosis. This review examines what we have learned about hepatic lipid metabolism and liver damage from the study of one-carbon metabolism thus far and highlights unexplored opportunities for future research.

scholarly journals ATRX limits the accessibility of histone H3-occupied HSV genomes during lytic infection

2021 ◽  
Vol 17 (4) ◽  
pp. e1009567
Author(s):  
Joseph M. Cabral ◽  
Camille H. Cushman ◽  
Catherine N. Sodroski ◽  
David M. Knipe
Keyword(s):  
Viral Replication ◽  
De Novo ◽  
Human Fibroblasts ◽  
Histone H3 ◽  
Gc Content ◽  
Lytic Infection ◽  
Nuclear Entry ◽  
Viral Dna ◽  
Total Histone ◽  
Viral Genomes

Histones are rapidly loaded on the HSV genome upon entry into the nucleus of human fibroblasts, but the effects of histone loading on viral replication have not been fully defined. We showed recently that ATRX is dispensable for de novo deposition of H3 to HSV genomes after nuclear entry but restricted infection through maintenance of viral heterochromatin. To further investigate the roles that ATRX and other histone H3 chaperones play in restriction of HSV, we infected human fibroblasts that were systematically depleted of nuclear H3 chaperones. We found that the ATRX/DAXX complex is unique among nuclear H3 chaperones in its capacity to restrict ICP0-null HSV infection. Only depletion of ATRX significantly alleviated restriction of viral replication. Interestingly, no individual nuclear H3 chaperone was required for deposition of H3 onto input viral genomes, suggesting that during lytic infection, H3 deposition may occur through multiple pathways. ChIP-seq for total histone H3 in control and ATRX-KO cells infected with ICP0-null HSV showed that HSV DNA is loaded with high levels of histones across the entire viral genome. Despite high levels of H3, ATAC-seq analysis revealed that HSV DNA is highly accessible, especially in regions of high GC content, and is not organized largely into ordered nucleosomes during lytic infection. ATRX reduced accessibility of viral DNA to the activity of a TN5 transposase and enhanced accumulation of viral DNA fragment sizes associated with nucleosome-like structures. Together, these findings support a model in which ATRX restricts viral infection by altering the structure of histone H3-loaded viral chromatin that reduces viral DNA accessibility for transcription. High GC rich regions of the HSV genome, especially the S component inverted repeats of the HSV-1 genome, show increased accessibility, which may lead to increased ability to transcribe the IE genes encoded in these regions during initiation of infection.

scholarly journals Serine and one-carbon metabolisms bring new therapeutic venues in prostate cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Carlo Ganini ◽  
Ivano Amelio ◽  
Riccardo Bertolo ◽  
Eleonora Candi ◽  
Angela Cappello ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Carbon Metabolism ◽  
Potential Role ◽  
De Novo ◽  
Cancer Pathogenesis ◽  
Gene And Protein Expression ◽  
Serine Pathway ◽  
One Carbon Metabolism ◽  
Serine Metabolism

AbstractSerine and one-carbon unit metabolisms are essential biochemical pathways implicated in fundamental cellular functions such as proliferation, biosynthesis of important anabolic precursors and in general for the availability of methyl groups. These two distinct but interacting pathways are now becoming crucial in cancer, the de novo cytosolic serine pathway and the mitochondrial one-carbon metabolism. Apart from their role in physiological conditions, such as epithelial proliferation, the serine metabolism alterations are associated to several highly neoplastic proliferative pathologies. Accordingly, prostate cancer shows a deep rearrangement of its metabolism, driven by the dependency from the androgenic stimulus. Several new experimental evidence describes the role of a few of the enzymes involved in the serine metabolism in prostate cancer pathogenesis. The aim of this study is to analyze gene and protein expression data publicly available from large cancer specimens dataset, in order to further dissect the potential role of the abovementioned metabolism in the complex reshaping of the anabolic environment in this kind of neoplasm. The data suggest a potential role as biomarkers as well as in cancer therapy for the genes (and enzymes) belonging to the one-carbon metabolism in the context of prostatic cancer.

Association of upregulation of serine and one carbon metabolism genes with shorter recurrence-free and overall survival in urothelial bladder cancer (UBC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 477-477
Author(s):  
Michael Lattanzi ◽  
Michael Pacold ◽  
Arjun Vasant Balar
Keyword(s):  
Bladder Cancer ◽  
Carbon Metabolism ◽  
De Novo ◽  
Univariate Analysis ◽  
The Cancer Genome Atlas ◽  
Expression Data ◽  
Key Enzyme ◽  
One Carbon Metabolism ◽  
Muscle Invasive

477 Background: Antimetabolites (e.g. methotrexate and gemcitabine) are not frequently used in the treatment of most solid tumors, but are effective in the treatment of UBC. Rapid cancer cell proliferation relies on an abundance of serine-derived one carbon units to support macromolecule synthesis. Specifically, PHGDH, which encodes a key enzyme of de novo serine synthesis, is amplified in breast cancer and in melanoma, and small molecule inhibitors of enzymes in this pathway are in early clinical development. However, the enzymes of serine and one carbon metabolism have not been widely investigated in UBC. Methods: We conducted an observational analysis of The Cancer Genome Atlas UBC cohort, focusing on gene expression data from a targeted panel indicated by Yang, et al. to be involved in serine and one carbon metabolism. Univariate Cox proportional hazard models were utilized to identify genes impacting OS and RFS, and a subsequent multivariate model was employed to control for inter-gene associations. Results: Expression data from 14 genes were analyzed among 436 UBC patients, of whom complete data were available for 422. At a median follow-up of 17 months, 188 of 422 patients had died. On univariate analysis, 7 of 14 genes were significantly associated with OS: PHGDH, PSPH, MTHFD1, MTHFD2, MTHFD1L, MTHFD2L, and ALDH1L2 (all P < 0.05). Interestingly, overexpression was associated with worse OS for all but one gene, MTHFD2L (HR 0.74), which is known to be underexpressed by cancer cells in favor of MTHFD2 (HR 1.21). In multivariate analysis, overexpression of PHGDH (HR 1.19, P = 0.008), MTHFD1 (HR 1.33, P = 0.041), and ALDH1L2 (HR 1.21, P < 0.001) were independent predictors of poor survival. RFS analysis was limited by missing data; nevertheless, univariate analyses found MTHFD1, MTHFD2, MTHFD1L, MTHFD2L, and ALDH1L2 to be associated with RFS (all P < 0.05). Conclusions: Within the limits of this observational study, these data suggest that serine and one carbon metabolism is important in the progression and prognosis of muscle-invasive bladder cancer. Subsequent in vitro analyses are needed to validate the prognostic and therapeutic significance of these findings.

Tetrahydrofolate biosynthesis and distribution in higher plants

2005 ◽  
Vol 33 (4) ◽  
pp. 758-762 ◽  
Author(s):  
T. Sahr ◽  
S. Ravanel ◽  
F. Rébeillé
Keyword(s):  
Carbon Metabolism ◽  
Growth And Development ◽  
De Novo ◽  
Higher Plants ◽  
The Other ◽  
Transfer Reactions ◽  
Intracellular Traffic ◽  
Vitamin B9 ◽  
Carbon Transfer ◽  
One Carbon Metabolism

One-carbon transfer reactions are mediated by H4F (tetrahydrofolate), a soluble coenzyme (vitamin B9) that is synthesized de novo by plants and microorganisms, and absorbed from the diet by animals. H4F synthesis in plants is quartered between the plastids, the cytosol and the mitochondria, a spatial distribution that is not observed in the other organisms and that suggests a complex intracellular traffic. Also, the activity of H4F synthesis fluctuates during plant growth, depending on the tissue and the developmental stage of the seedling, thus illustrating the flexibility of one-carbon metabolism in these organisms. This paper will focus on our recent knowledge about H4F synthesis in the plant cell and will briefly describe the activity of the pathway during the growth and development of the seedling.

scholarly journals Morphological, Biochemical, and Functional Study of Viral Replication Compartments Isolated from Adenovirus-Infected Cells

2016 ◽  
Vol 90 (7) ◽  
pp. 3411-3427 ◽  
Author(s):  
Paloma Hidalgo ◽  
Lourdes Anzures ◽  
Armando Hernández-Mendoza ◽  
Adán Guerrero ◽  
Christopher D. Wood ◽  
...  
Keyword(s):  
Viral Replication ◽  
Host Cell ◽  
Viral Genome ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Functional Study ◽  
Viral Dna ◽  
Superresolution Microscopy ◽  
Infected Cells ◽  
Efficient Viral Replication

ABSTRACTAdenovirus (Ad) replication compartments (RC) are nuclear microenvironments where the viral genome is replicated and a coordinated program of late gene expression is established. These virus-induced nuclear sites seem to behave as central hubs for the regulation of virus-host cell interactions, since proteins that promote efficient viral replication as well as factors that participate in the antiviral response are coopted and concentrated there. To gain further insight into the activities of viral RC, here we report, for the first time, the morphology, composition, and activities of RC isolated from Ad-infected cells. Morphological analyses of isolated RC particles by superresolution microscopy showed that they were indistinguishable from RC within infected cells and that they displayed a dynamic compartmentalization. Furthermore, the RC-containing fractions (RCf) proved to be functional, as they directedde novosynthesis of viral DNA and RNA as well as RNA splicing, activities that are associated with RCin vivo. A detailed analysis of the production of viral late mRNA from RCf at different times postinfection revealed that viral mRNA splicing occurs in RC and that the synthesis, posttranscriptional processing, and release from RC to the nucleoplasm of individual viral late transcripts are spatiotemporally separate events. The results presented here demonstrate that RCf are a powerful system for detailed study into RC structure, composition, and activities and, as a result, the determination of the molecular mechanisms that induce the formation of these viral sites of adenoviruses and other nuclear-replicating viruses.IMPORTANCERC may represent molecular hubs where many aspects of virus-host cell interaction are controlled. Here, we show by superresolution microscopy that RCf have morphologies similar to those of RC within Ad-infected cells and that they appear to be compartmentalized, as nucleolin and DBP display different localization in the periphery of these viral sites. RCf proved to be functional, as they directde novosynthesis of viral DNA and mRNA, allowing the detailed study of the regulation of viral genome replication and expression. Furthermore, we show that the synthesis and splicing of individual viral late mRNA occurs in RC and that they are subject to different temporal patterns of regulation, from their synthesis to their splicing and release from RC to the nucleoplasm. Hence, RCf represent a novel system to study molecular mechanisms that are orchestrated in viral RC to take control of the infected cell and promote an efficient viral replication cycle.

Canadian Society of Plant Physiologists Gold Medal Review / Synthèse médaillée d'or de la Société canadienne physiologie végétaleThe fascinating world of folate and one-carbon metabolism

2000 ◽  
Vol 78 (6) ◽  
pp. 691-708 ◽  
Author(s):  
Edwin A Cossins
Keyword(s):  
Carbon Metabolism ◽  
De Novo ◽  
Normal Growth ◽  
Gold Medal ◽  
Animal Cells ◽  
Isolation And Characterization ◽  
Folate Biosynthesis ◽  
One Carbon Metabolism ◽  
Société Canadienne ◽  
Antifolate Drugs

Folate was first isolated from spinach leaves in 1941 and characterized as pteroylglutamic acid. Although plants, fungi, and bacteria synthesize folate de novo, animal cells lack key enzymes of the folate biosynthetic pathway and a dietary source of folate is required for normal growth and development. Folates have importance in human nutrition, health, and disease, and antifolate drugs are commonly used in cancer chemotherapy. In the majority of living cells folates occur as one-carbon substituted tetrahydropteroylpolyglutamate derivatives. These folates donate one-carbon groups during the synthesis of purines, formylmethionyl-tRNA, thymidylate, serine, and methionine. In the last 30 years, research on the folate biochemistry of plant species has intensified and been aided by the development of improved methods for folate isolation and characterization. These studies have resulted in basic information on the nature of plant folylpolyglutamates, folate biosynthesis, the enzymology of several folate-dependent reactions, and the roles of chloroplasts, mitochondria, and the cytosol in the pathways of one-carbon metabolism.Key words: plants, folates, folate biosynthesis, folate-dependent enzymes, one-carbon metabolism.

scholarly journals A hybrid stochastic model of folate-mediated one-carbon metabolism: Effect of the common C677T MTHFR variant on de novo thymidylate biosynthesis

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Karla Misselbeck ◽  
Luca Marchetti ◽  
Martha S. Field ◽  
Marco Scotti ◽  
Corrado Priami ◽  
...  
Keyword(s):  
Stochastic Model ◽  
Carbon Metabolism ◽  
De Novo ◽  
C677t Mthfr ◽  
The Common ◽  
One Carbon Metabolism

scholarly journals Taking over Cellular Energy-Metabolism for TBSV Replication: The High ATP Requirement of an RNA Virus within the Viral Replication Organelle

Viruses ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 56 ◽  
Author(s):  
Peter D. Nagy ◽  
Wenwu Lin
Keyword(s):  
Viral Replication ◽  
Rna Virus ◽  
Energy Requirement ◽  
Replication Proteins ◽  
Replication Process ◽  
Small Plant ◽  
Cellular Energy ◽  
Energy Needs ◽  
Infected Cells ◽  
Host Metabolism

Recent discoveries on virus-driven hijacking and compartmentalization of the cellular glycolytic and fermentation pathways to support robust virus replication put the spotlight on the energy requirement of viral processes. The active recruitment of glycolytic enzymes in combination with fermentation enzymes by the viral replication proteins emphasizes the advantages of producing ATP locally within viral replication structures. This leads to a paradigm shift in our understanding of how viruses take over host metabolism to support the virus’s energy needs during the replication process. This review highlights our current understanding of how a small plant virus, Tomato bushy stunt virus, exploits a conserved energy-generating cellular pathway during viral replication. The emerging picture is that viruses not only rewire cellular metabolic pathways to obtain the necessary resources from the infected cells but the fast replicating viruses might have to actively hijack and compartmentalize the energy-producing enzymes to provide a readily available source of ATP for viral replication process.

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