Inhibition of aldolase A blocks biogenesis of ATP and attenuates Japanese encephalitis virus production

Tien, Chih-Feng; Cheng, Shih-Ching; Ho, Yen‐Peng; Chen, Yi-Shiuan; Hsu, Jung-Hsin; Chang, Ruey-Yi

doi:10.1016/j.bbrc.2013.11.128

Cited by 12 publications

(6 citation statements)

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“…Under the well-fed condition, glucose is the major substrate for ATP production, but when glucose level is low or with excess fatty acid content, fatty acids will become the alternative source for energy production [ 36 , 37 ]. JEV infection consumes ATP [ 68 ], so ATP levels were lower in JEV-infected cells as compared to mock ( S14 Fig ). Because of LCFA β-oxidation impairment by JEV, further reduction of ATP was seen in cells cultured with PA-BSA ( S14 Fig ).…”

Section: Discussionmentioning

confidence: 99%

“…Normally, glucose is mainly broken down by oxidative phosphorylation in mitochondria, but under hypoxia and stress conditions such as virus infection [ 69 ], glycolysis occurring in cytoplasm will dominate [ 70 , 71 ]. For example, HCV and HCMV infection induces glycolysis [ 72 , 73 ] and the activity of some glycolysis enzymes is increased during JEV infection [ 68 , 74 ]. Glycolysis produces lactate and causes acidification of the extracellular space, called lactic acidosis [ 75 ], seen in patients with LCFA β-oxidation deficiency [ 76 , 77 ] and Japanese encephalitis (JE) [ 78 ].…”

Section: Discussionmentioning

confidence: 99%

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Japanese Encephalitis Virus Nonstructural Protein NS5 Interacts with Mitochondrial Trifunctional Protein and Impairs Fatty Acid β-Oxidation

et al. 2015

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Infection with Japanese encephalitis virus (JEV) can induce the expression of pro-inflammatory cytokines and cause acute encephalitis in humans. β-oxidation breaks down fatty acids for ATP production in mitochondria, and impaired β-oxidation can induce pro-inflammatory cytokine expression. To address the role of fatty-acid β-oxidation in JEV infection, we measured the oxygen consumption rate of mock- and JEV-infected cells cultured with or without long chain fatty acid (LCFA) palmitate. Cells with JEV infection showed impaired LCFA β-oxidation and increased interleukin 6 (IL-6) and tumor necrosis factor α (TNF-α) expression. JEV nonstructural protein 5 (NS5) interacted with hydroxyacyl-CoA dehydrogenase α and β subunits, two components of the mitochondrial trifunctional protein (MTP) involved in LCFA β-oxidation, and NS5 proteins were detected in mitochondria and co-localized with MTP. LCFA β-oxidation was impaired and higher cytokines were induced in cells overexpressing NS5 protein as compared with control cells. Deletion and mutation studies showed that the N-terminus of NS5 was involved in the MTP association, and a single point mutation of NS5 residue 19 from methionine to alanine (NS5-M19A) reduced its binding ability with MTP. The recombinant JEV with NS5-M19A mutation (JEV-NS5-M19A) was less able to block LCFA β-oxidation and induced lower levels of IL-6 and TNF-α than wild-type JEV. Moreover, mice challenged with JEV-NS5-M19A showed less neurovirulence and neuroinvasiveness. We identified a novel function of JEV NS5 in viral pathogenesis by impairing LCFA β-oxidation and inducing cytokine expression by association with MTP.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Japanese Encephalitis Virus Nonstructural Protein NS5 Interacts with Mitochondrial Trifunctional Protein and Impairs Fatty Acid β-Oxidation

et al. 2015

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“…Different steps in viral replication including DNA packaging and capsid maturation require ATP [26]. Analysis of the ATP production during the course of BAdV-3 infection showed a steady increase in the ATP production till 18 th hpi, when the production of progeny virus particles is at its peak.…”

Section: Discussionmentioning

confidence: 99%

Effect of bovine adenovirus 3 on mitochondria

Anand

Singh

Gaba

et al. 2014

Vet Res

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Viruses alter the structure and the function of mitochondria for survival. Electron microscopy analysis of the cells infected with bovine adenovirus 3 revealed extensive damage to the inner mitochondrial membrane characterized by dissolution of the cristae and amorphous appearance of mitochondrial matrix with little or no damage to the outer mitochondrial membrane. There were fewer cristae with altered morphology. Potential patches of protein synthesis machinary around mitochondria could be observed at 12 hours post infection (hpi). At 24 hpi, the multi vascular bodies were evident throughout the infected cell. ATP production, mitochondrial Ca2+ and mitochondrial membrane potential (MMP) peaked at 18 hpi but decreased significantly at 24 hpi. This decrease coincided with the increased production of superoxide (SO) and reactive oxygen species (ROS), at 24 hpi indicating acute oxidative stress in the cells and suggesting a complete failure of the cellular homeostatic machinary. The results reveal an intericate relationship between Ca2+ homeostasis, the ATP generation ability of cells, SO and ROS production, and regulation of MMP following infection by bovine adenovirus 3.

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“…Human ALDOA can bind to the untranslated regions (UTRs) of the Japanese encephalitis virus (JEV) RNA antigenome and can influence viral replication. Expression of the viral nonstructural protein 5 (NS5) reduces to ∼41% in ALDOA-knockout human embryonic kidney (HEK238T) cells ( Tien et al, 2014 ). In addition, JEV infection increased expression of ALDOA by 33% in these cells.…”

Section: Non-canonical Functions Of Intracellular Aldolasesmentioning

confidence: 99%

Multifunctional Fructose 1,6-Bisphosphate Aldolase as a Therapeutic Target

Pirovich

Da’dara

Skelly

2021

Front. Mol. Biosci.

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Fructose 1,6-bisphosphate aldolase is a ubiquitous cytosolic enzyme that catalyzes the fourth step of glycolysis. Aldolases are classified into three groups: Class-I, Class-IA, and Class-II; all classes share similar structural features but low amino acid identity. Apart from their conserved role in carbohydrate metabolism, aldolases have been reported to perform numerous non-enzymatic functions. Here we review the myriad “moonlighting” functions of this classical enzyme, many of which are centered on its ability to bind to an array of partner proteins that impact cellular scaffolding, signaling, transcription, and motility. In addition to the cytosolic location, aldolase has been found the extracellular surface of several pathogenic bacteria, fungi, protozoans, and metazoans. In the extracellular space, the enzyme has been reported to perform virulence-enhancing moonlighting functions e.g., plasminogen binding, host cell adhesion, and immunomodulation. Aldolase’s importance has made it both a drug target and vaccine candidate. In this review, we note the several inhibitors that have been synthesized with high specificity for the aldolases of pathogens and cancer cells and have been shown to inhibit classical enzyme activity and moonlighting functions. We also review the many trials in which recombinant aldolases have been used as vaccine targets against a wide variety of pathogenic organisms including bacteria, fungi, and metazoan parasites. Most of such trials generated significant protection from challenge infection, correlated with antigen-specific cellular and humoral immune responses. We argue that refinement of aldolase antigen preparations and expansion of immunization trials should be encouraged to promote the advancement of promising, protective aldolase vaccines.

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Inhibition of aldolase A blocks biogenesis of ATP and attenuates Japanese encephalitis virus production

Cited by 12 publications

References 30 publications

Japanese Encephalitis Virus Nonstructural Protein NS5 Interacts with Mitochondrial Trifunctional Protein and Impairs Fatty Acid β-Oxidation

Japanese Encephalitis Virus Nonstructural Protein NS5 Interacts with Mitochondrial Trifunctional Protein and Impairs Fatty Acid β-Oxidation

Effect of bovine adenovirus 3 on mitochondria

Multifunctional Fructose 1,6-Bisphosphate Aldolase as a Therapeutic Target

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