bims-polyam 2019-07-28 papers

J Virol. 2019 Jul 24. pii: JVI.01054-19. [Epub ahead of print]

Polyamine depletion abrogates enterovirus cellular attachment.

Thomas M Kicmal, Patrick M Tate, Courtney N Dial, Jeremy J Esin, Bryan C Mounce.

Polyamines are small polycationic molecules with flexible carbon chains that are found in all eukaryotic cells. Polyamines are involved in the regulation of many host processes and have been shown to be implicated in viral replication. Depletion of polyamine pools in cells with FDA approved drugs restricts replication of diverse RNA viruses. Viruses can exploit host polyamines to facilitate nucleic acid packaging, transcription, and translation, but other mechanisms remain largely unknown. Picornaviruses, including Coxsackievirus B3 (CVB3), are sensitive to depletion of polyamines and remain a significant public health threat. We employed CVB3 as a model system to investigate a potential pro-viral role for polyamines using a forward screen. Passaging CVB3 in polyamine depleted cells generated a mutation in capsid protein VP3 at residue 234. We show this mutation confers resistance to polyamine depletion. Through attachment assays, we demonstrate that polyamine depletion limits CVB3 attachment to susceptible cells, which is rescued by incubating virus with polyamines. Further, the capsid mutant rescues this inhibition in polyamine depleted cells. More divergent viruses also exhibited reduced attachment to polyamine depleted cells, suggesting that polyamines may facilitate attachment of diverse RNA viruses. These studies inform additional mechanisms of action for polyamine-depleting pharmaceuticals with implications for potential antiviral therapies.IMPORTANCE Enteroviruses are significant human pathogens that can cause severe disease. These viruses rely on polyamines, small positively-charged molecules, for robust replication, and polyamine depletion limits infection in vitro and in vivo The mechanisms by which polyamines enhance enteroviral replication are unknown. Here, we describe how Coxsackievirus B3 (CVB3) utilizes polyamines to attach to susceptible cells and initiate infection. Using a forward genetic screen, we identified a mutation in a receptor-binding amino acid that promotes infection of polyamine-depleted cells. These data suggest that inhibiting polyamine biosynthesis pharmacologically may combat virus infection by preventing virus attachment to susceptible cells.

DOI: https://doi.org/10.1128/JVI.01054-19

Front Plant Sci. 2019 ;10 816

Transcriptional Modulation of Polyamine Metabolism in Fruit Species Under Abiotic and Biotic Stress.

Ana Margarida Fortes, Patricia Agudelo-Romero, Diana Pimentel, Noam Alkan.

Polyamines are growth regulators that have been widely implicated in abiotic and biotic stresses. They are also associated with fruit set, ripening, and regulation of fruit quality-related traits. Modulation of their content confers fruit resilience, with polyamine application generally inhibiting postharvest decay. Changes in the content of free and conjugated polyamines in response to stress are highly dependent on the type of abiotic stress applied or the lifestyle of the pathogen. Recent studies suggest that exogenous application of polyamines or modulation of polyamine content by gene editing can confer tolerance to multiple abiotic and biotic stresses simultaneously. In this review, we explore data on polyamine synthesis and catabolism in fruit related to pre- and postharvest stresses. Studies of mutant plants, priming of stress responses, and treatments with polyamines and polyamine inhibitors indicate that these growth regulators can be manipulated to increase fruit productivity with reduced use of pesticides and therefore, under more sustainable conditions.

Keywords: abiotic stress; biotic stress; fruit ripening; grape; polyamine; tomato

DOI: https://doi.org/10.3389/fpls.2019.00816

PLoS Genet. 2019 Jul 24. 15(7): e1008292

Polyamine uptake transporter 2 (put2) and decaying seeds enhance phyA-mediated germination by overcoming PIF1 repression of germination.

Woohyun Kim, Sanja Ćavar Zeljković, Urszula Piskurewicz, Christian Megies, Petr Tarkowski, Luis Lopez-Molina.

Red light promotes germination after activating phytochrome phyB, which destabilizes the germination repressor PIF1. Early upon seed imbibition, canopy light, unfavorable for photosynthesis, represses germination by stabilizing PIF1 after inactivating phyB. Paradoxically, later upon imbibition, canopy light stimulates germination after activating phytochrome phyA. phyA-mediated germination is poorly understood and, intriguingly, is inefficient, compared to phyB-mediated germination, raising the question of its physiological significance. A genetic screen identified polyamine uptake transporter 2 (put2) mutants that overaccumulate polyamines, a class of antioxidant polycations implicated in numerous cellular functions, which we found promote phyA-mediated germination. In WT seeds, our data suggest that canopy light represses polyamines accumulation through PIF1 while red light promotes polyamines accumulation. We show that canopy light also downregulates PIF1 levels, through phyA; however, PIF1 reaccumulates rapidly, which limits phyA-mediated germination. High polyamines levels in decaying seeds bypass PIF1 repression of germination and stimulate phyA-mediated germination, suggesting an adaptive mechanism promoting survival when viability is compromised.

DOI: https://doi.org/10.1371/journal.pgen.1008292

Aging (Albany NY). 2019 Jul 24.

The metabolomic signature of extreme longevity: naked mole rats versus mice.

Mélanie Viltard, Sylvère Durand, Maria Pérez-Lanzón, Fanny Aprahamian, Deborah Lefevre, Christine Leroy, Frank Madeo, Guido Kroemer, Gérard Friedlander.

The naked mole-rat (Heterocephalus glaber) is characterized by a more than tenfold higher life expectancy compared to another rodent species of the same size, namely, the laboratory mouse (Mus musculus). We used mass spectrometric metabolomics to analyze circulating plasma metabolites in both species at different ages. Interspecies differences were much more pronounced than age-associated alterations in the metabolome. Such interspecies divergences affected multiple metabolic pathways involving amino, bile and fatty acids as well as monosaccharides and nucleotides. The most intriguing metabolites were those that had previously been linked to pro-health and antiaging effects in mice and that were significantly increased in the long-lived rodent compared to its short-lived counterpart. This pattern applies to α-tocopherol (also known as vitamin E) and polyamines (in particular cadaverine, N8-acetylspermidine and N1,N8-diacetylspermidine), all of which were more abundant in naked mole-rats than in mice. Moreover, the age-associated decline in spermidine and N1-acetylspermidine levels observed in mice did not occur, or is even reversed (in the case of N1-acetylspermidine) in naked mole-rats. In short, the present metabolomics analysis provides a series of testable hypotheses to explain the exceptional longevity of naked mole-rats.

Keywords: antioxidants; autophagy; catabolism; meta-organism; microbiota; spermidine

DOI: https://doi.org/10.18632/aging.102116

Toxicol Appl Pharmacol. 2019 Jul 16. pii: S0041-008X(19)30274-1. [Epub ahead of print]379 114666

Untargeted liquid chromatography-mass spectrometry metabolomics to assess drug-induced cholestatic features in HepaRG® cells.

Matthias Cuykx, Charlie Beirnaert, Robim M Rodrigues, Kris Laukens, Tamara Vanhaecke, Adrian Covaci.

Cholestasis is a liver disease associated with retention of bile in the liver, which leads to local hepatic inflammation and severe liver damage. In order to investigate the mode of action of drug-induced cholestasis, in vitro models have shown to be able to recapitulate important elements of this disease. In this study, we applied untargeted metabolomics to investigate the metabolic perturbances in HepaRG® cells exposed for 24 h and 72 h to bosentan, a cholestatic reference toxicant. Intracellular profiles were extracted and analysed with liquid chromatography and accurate-mass spectrometry. Metabolites of interest were selected using partial least-squares discriminant analysis and random forest classifier models. The observed metabolic patterns associated with cholestasis in vitro were complex. Acute (24 h) exposure revealed metabolites related to apoptosis, such as ceramide and triglyceride accumulation, in combination with phosphatidylethanolamine, choline and carnitine depletion. Metabolomic alterations during exposure to lower dosages and a prolonged exposure (72 h) included carnitine upregulation and changes in the polyamine metabolism. These metabolites were linked to changes in phospholipid metabolism, mitochondrial pathways and energy homeostasis. The metabolic changes confirmed the mitotoxic effects of bosentan and revealed the potential involvement of phospholipid metabolism as part of the mode of action of drug-induced cholestasis.

Keywords: Bosentan; Drug-induced cholestasis; HepaRG; In vitro; Liquid chromatography-mass spectrometry; Metabolomics

DOI: https://doi.org/10.1016/j.taap.2019.114666

Protoplasma. 2019 Jul 24.

Putrescine modifies the pollen tube growth of tea (Camellia sinensis) by affecting actin organization and cell wall structure.

Aslıhan Çetinbaş-Genç.

The aim of the current study was to examine the effect of different exogenous putrescine concentrations (200, 400, 600, and 800 μM) on the tea pollen performance. It was shown that putrescine has a dose-dependent effect on pollen performance. Results exhibited that pollen germination and tube elongation were induced by 200 and 400 μM putrescine treatment, especially, 400 μM putrescine-enhanced pollen performance. However, pollen performance was inhibited by higher concentrations of putrescine. Putrescine concentrations above 400 μM changed the actin filament distribution in pollen tubes by affecting the distribution of sucrose synthase enzyme. Alterations of the distribution on sucrose synthase enzyme also caused the alterations in the dispersion of cellulose and callose in the cell wall, and morphological alterations such as balloon-shaped and snake-shaped pollen tube tip accompanied them. Moreover, putrescine concentrations above 400 μM caused a decrease of ROS level in apex and led to chromatin condensation of the generative nucleus. In conclusion, exogenous putrescine application can be used as a pollen performance enhancer at low concentrations while the high concentrations cause adverse effects reducing fertilization success.

Keywords: Actin cytoskeleton; Camellia sinensis; Cell wall; Pollen tube elongation; Polyamines; Reactive oxygen species

DOI: https://doi.org/10.1007/s00709-019-01422-x