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1.
Traffic ; 14(11): 1182-91, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23944656

RESUMO

Gangliosides, glycosphingolipids containing sialic acid moieties, are well known mediators of transmembrane signaling and endocytosis at the plasma membrane. However, little is known about their precise regulatory role at the cell periphery for intracellular sorting of extracellular cargo. Here we inspected published scientific literature for two types of cargoes, namely bacterial toxins and viruses, regarding their usage of gangliosides. We derived a rather simple yet surprisingly consistent framework to classify 20 viruses from 12 different families and five type AB bacterial toxins into two broad categories. We propose that gangliosides with terminally attached sialic acids classify cargo for uptake and trafficking early in the endocytic pathway while gangliosides with internally attached sialic acids associate with uptake and trafficking of cargo late in the endocytic system. Our study provides a testable hypothesis for future investigations into a wide range of trafficking events. It could be utilized as a framework for other intracellular pathogens where lipids are known to be involved in recognition and trafficking. For instance, predictions can be put forward and evaluated based on ganglioside binding patterns and intracellular trafficking routes. Finally, incorporation of our classifier into large scale systems-biology studies could help reveal related molecular determinants in subcellular sorting.


Assuntos
Endocitose , Glicoesfingolipídeos/metabolismo , Ácido N-Acetilneuramínico/química , Animais , Toxinas Bacterianas/classificação , Toxinas Bacterianas/metabolismo , Membrana Celular/química , Membrana Celular/metabolismo , Membrana Celular/virologia , Endossomos/metabolismo , Endossomos/virologia , Glicoesfingolipídeos/química , Glicoesfingolipídeos/classificação , Interações Hospedeiro-Patógeno , Humanos , Ácido N-Acetilneuramínico/metabolismo , Transporte Proteico , Vírus/classificação , Vírus/metabolismo
2.
J Lipid Res ; 55(7): 1357-65, 2014 07.
Artigo em Inglês | MEDLINE | ID: mdl-24868094

RESUMO

Influenza virus acquires a host-derived lipid envelope during budding, yet a convergent view on the role of host lipid metabolism during infection is lacking. Using a mass spectrometry-based lipidomics approach, we provide a systems-scale perspective on membrane lipid dynamics of infected human lung epithelial cells and purified influenza virions. We reveal enrichment of the minor peroxisome-derived ether-linked phosphatidylcholines relative to bulk ester-linked phosphatidylcholines in virions as a unique pathogenicity-dependent signature for influenza not found in other enveloped viruses. Strikingly, pharmacological and genetic interference with peroxisomal and ether lipid metabolism impaired influenza virus production. Further integration of our lipidomics results with published genomics and proteomics data corroborated altered peroxisomal lipid metabolism as a hallmark of influenza virus infection in vitro and in vivo. Influenza virus may therefore tailor peroxisomal and particularly ether lipid metabolism for efficient replication.


Assuntos
Vírus da Influenza A Subtipo H1N1/fisiologia , Peroxissomos/metabolismo , Fosfatidilcolinas/metabolismo , Replicação Viral/fisiologia , Células A549 , Animais , Células CHO , Cricetinae , Cricetulus , Cães , Humanos , Células Madin Darby de Rim Canino , Peroxissomos/virologia
3.
J Biol Chem ; 287(48): 40525-34, 2012 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-23035113

RESUMO

BACKGROUND: Dengue virus surface proteins, envelope (E) and pre-membrane (prM), undergo rearrangement during the maturation process at acidic condition. RESULTS: prM-stem region binds tighter to both E protein and lipid membrane when environment becomes acidic. CONCLUSION: At acidic condition, E proteins are attracted to the membrane-associated prM-stem. SIGNIFICANCE: prM-stem region induces virus structural changes during maturation. Newly assembled dengue viruses (DENV) undergo maturation to become infectious particles. The maturation process involves major rearrangement of virus surface premembrane (prM) and envelope (E) proteins. The prM-E complexes on immature viruses are first assembled as trimeric spikes in the neutral pH environment of the endoplasmic reticulum. When the virus is transported to the low pH environment of the exosomes, these spikes rearrange into dimeric structures, which lie parallel to the virus lipid envelope. The proteins involved in driving this process are unknown. Previous cryoelectron microscopy studies of the mature DENV showed that the prM-stem region (residues 111-131) is membrane-associated and may interact with the E proteins. Here we investigated the prM-stem region in modulating the virus maturation process. The binding of the prM-stem region to the E protein was shown to increase significantly at low pH compared with neutral pH in ELISAs and surface plasmon resonance studies. In addition, the affinity of the prM-stem region for the liposome, as measured by fluorescence correlation spectroscopy, was also increased when pH is lowered. These results suggest that the prM-stem region forms a tight association with the virus membrane and attracts the associated E protein in the low pH environment of exosomes. This will lead to the surface protein rearrangement observed during maturation.


Assuntos
Vírus da Dengue/fisiologia , Dengue/virologia , Proteínas do Envelope Viral/química , Proteínas do Envelope Viral/metabolismo , Montagem de Vírus , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Linhagem Celular , Vírus da Dengue/química , Vírus da Dengue/genética , Humanos , Dados de Sequência Molecular , Alinhamento de Sequência , Proteínas do Envelope Viral/genética
4.
Cell Syst ; 7(1): 49-62.e8, 2018 07 25.
Artigo em Inglês | MEDLINE | ID: mdl-29960885

RESUMO

Altered glycolysis is a hallmark of diseases including diabetes and cancer. Despite intensive study of the contributions of individual glycolytic enzymes, systems-level analyses of flux control through glycolysis remain limited. Here, we overexpress in two mammalian cell lines the individual enzymes catalyzing each of the 12 steps linking extracellular glucose to excreted lactate, and find substantial flux control at four steps: glucose import, hexokinase, phosphofructokinase, and lactate export (and not at any steps of lower glycolysis). The four flux-controlling steps are specifically upregulated by the Ras oncogene: optogenetic Ras activation rapidly induces the transcription of isozymes catalyzing these four steps and enhances glycolysis. At least one isozyme catalyzing each of these four steps is consistently elevated in human tumors. Thus, in the studied contexts, flux control in glycolysis is concentrated in four key enzymatic steps. Upregulation of these steps in tumors likely underlies the Warburg effect.


Assuntos
Glicólise/fisiologia , Hexoquinase/metabolismo , Fosfofrutoquinase-1/metabolismo , Animais , Transporte Biológico , Linhagem Celular , Genes ras/genética , Genes ras/fisiologia , Glucose/metabolismo , Glicólise/genética , Células HEK293 , Hexoquinase/genética , Humanos , Isoenzimas/metabolismo , Ácido Láctico/biossíntese , Mamíferos , Camundongos , Modelos Biológicos , Células NIH 3T3 , Neoplasias/enzimologia
5.
Cell Host Microbe ; 13(4): 375-7, 2013 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-23601099

RESUMO

Virus replication requires lipid metabolism, but how lipids mediate virus infection remains obscure. In this issue, Amini-Bavil-Olyaee et al. (2013) reveal that IFITM proteins disturb cholesterol homeostasis to block virus entry. Previously, in Cell, Morita and colleagues (2013) showed the antiviral potency of the lipid mediator protectin D1.

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