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1.
BMC Biol ; 17(1): 59, 2019 07 18.
Article in English | MEDLINE | ID: mdl-31319842

ABSTRACT

This review discusses the current state of the viral metabolism field and gaps in knowledge that will be important for future studies to investigate. We discuss metabolic rewiring caused by viruses, the influence of oncogenic viruses on host cell metabolism, and the use of viruses as guides to identify critical metabolic nodes for cancer anabolism. We also discuss the need for more mechanistic studies identifying viral proteins responsible for metabolic hijacking and for in vivo studies of viral-induced metabolic rewiring. Improved technologies for detailed metabolic measurements and genetic manipulation will lead to important discoveries over the next decade.


Subject(s)
Neoplasms/metabolism , Viruses/metabolism , Host-Pathogen Interactions , Metabolic Networks and Pathways , Neoplasms/virology
2.
Cell Metab ; 29(5): 1206-1216.e4, 2019 05 07.
Article in English | MEDLINE | ID: mdl-30827860

ABSTRACT

Zika virus is a pathogen that poses serious consequences, including congenital microcephaly. Although many viruses reprogram host cell metabolism, whether Zika virus alters cellular metabolism and the functional consequences of Zika-induced metabolic changes remain unknown. Here, we show that Zika virus infection differentially reprograms glucose metabolism in human versus C6/36 mosquito cells by increasing glucose use in the tricarboxylic acid cycle in human cells versus increasing glucose use in the pentose phosphate pathway in mosquito cells. Infection of human cells selectively depletes nucleotide triphosphate levels, leading to elevated AMP/ATP ratios, AMP-activated protein kinase (AMPK) phosphorylation, and caspase-mediated cell death. AMPK is also phosphorylated in Zika virus-infected mouse brain. Inhibiting AMPK in human cells decreases Zika virus-mediated cell death, whereas activating AMPK in mosquito cells promotes Zika virus-mediated cell death. These findings suggest that the differential metabolic reprogramming during Zika virus infection of human versus mosquito cells determines whether cell death occurs.


Subject(s)
Aedes/cytology , Cell Death , Epithelial Cells/metabolism , Epithelial Cells/microbiology , Fibroblasts/metabolism , Fibroblasts/microbiology , Zika Virus Infection/metabolism , Zika Virus/metabolism , AMP-Activated Protein Kinases/antagonists & inhibitors , AMP-Activated Protein Kinases/metabolism , Animals , Chlorocebus aethiops , Citric Acid Cycle , Foreskin/cytology , Glucose/metabolism , Humans , Male , Mice , Mice, Knockout , Pentose Phosphate Pathway , Phosphorylation , Receptor, Interferon alpha-beta/genetics , Retinal Pigment Epithelium/cytology , Vero Cells , Zika Virus Infection/virology
3.
Elife ; 52016 09 01.
Article in English | MEDLINE | ID: mdl-27585295

ABSTRACT

A well-characterized metabolic landmark for aggressive cancers is the reprogramming from oxidative phosphorylation to aerobic glycolysis, referred to as the Warburg effect. Models mimicking this process are often incomplete due to genetic complexities of tumors and cell lines containing unmapped collaborating mutations. In order to establish a system where individual components of oncogenic signals and metabolic pathways can be readily elucidated, we induced a glycolytic tumor in the Drosophila wing imaginal disc by activating the oncogene PDGF/VEGF-receptor (Pvr). This causes activation of multiple oncogenic pathways including Ras, PI3K/Akt, Raf/ERK, Src and JNK. Together this network of genes stabilizes Hifα (Sima) that in turn, transcriptionally up-regulates many genes encoding glycolytic enzymes. Collectively, this network of genes also causes inhibition of pyruvate dehydrogenase (PDH) activity resulting in diminished ox-phos levels. The high ROS produced during this process functions as a feedback signal to consolidate this metabolic reprogramming.


Subject(s)
Gene Expression Regulation, Neoplastic , Glycolysis , Neoplasms/metabolism , Neoplasms/physiopathology , Animals , DNA-Binding Proteins/biosynthesis , Disease Models, Animal , Drosophila , Drosophila Proteins/biosynthesis , Gene Regulatory Networks , Oxidative Phosphorylation , Pyruvate Dehydrogenase Complex/biosynthesis
4.
Nat Commun ; 6: 8873, 2015 Nov 12.
Article in English | MEDLINE | ID: mdl-26561297

ABSTRACT

Viruses rewire host cell glucose and glutamine metabolism to meet the bioenergetic and biosynthetic demands of viral propagation. However, the mechanism by which viruses reprogram glutamine metabolism and the metabolic fate of glutamine during adenovirus infection have remained elusive. Here, we show MYC activation is necessary for adenovirus-induced upregulation of host cell glutamine utilization and increased expression of glutamine transporters and glutamine catabolism enzymes. Adenovirus-induced MYC activation promotes increased glutamine uptake, increased use of glutamine in reductive carboxylation and increased use of glutamine in generating hexosamine pathway intermediates and specific amino acids. We identify glutaminase (GLS) as a critical enzyme for optimal adenovirus replication and demonstrate that GLS inhibition decreases replication of adenovirus, herpes simplex virus 1 and influenza A in cultured primary cells. Our findings show that adenovirus-induced reprogramming of glutamine metabolism through MYC activation promotes optimal progeny virion generation, and suggest that GLS inhibitors may be useful therapeutically to reduce replication of diverse viruses.


Subject(s)
Adenoviridae/physiology , Glutamine/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Virus Replication/physiology , Cell Line , Humans , Mutation , Proto-Oncogene Proteins c-myc/genetics
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