Mutational analysis of putative phosphate- and proton-binding sites in the <i>Saccharomyces cerevisiae</i> Pho84 phosphate:H+ transceptor and its effect on signalling to the PKA and <i>PHO</i> pathways

Samyn, Dieter R.; Ruiz-Pavón, Lorena; Andersson, Michael R.; Popova, Yulia; Thevelein, Johan M.; Persson, Bengt L.

doi:10.1042/bj20112086

Cited by 52 publications

(67 citation statements)

References 42 publications

(52 reference statements)

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“…Pho84 functions as both as a transporter and receptor (a transceptor) for phosphate in S. cerevisiae (84,85). The transport activity is not essential for the sensor function of Pho84, and targets of the PKA pathway are known to be regulated by the sensing activity of Pho84, thus indicating an influence on PKA activity (51,52,86,87). Our previous work also revealed that deletions in genes encoding components of PKA perturbed phosphate metabolism and polyphosphate formation in U maydis (35,36).…”

Section: Discussionmentioning

confidence: 93%

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Defects in Phosphate Acquisition and Storage Influence Virulence of Cryptococcus neoformans

et al. 2014

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Nutrient acquisition and sensing are critical aspects of microbial pathogenesis. Previous transcriptional profiling indicated that the fungal pathogen Cryptococcus neoformans, which causes meningoencephalitis in immunocompromised individuals, encounters phosphate limitation during proliferation in phagocytic cells. We therefore tested the hypothesis that phosphate acquisition and polyphosphate metabolism are important for cryptococcal virulence. Deletion of the high-affinity uptake system interfered with growth on low-phosphate medium, perturbed the formation of virulence factors (capsule and melanin), reduced survival in macrophages, and attenuated virulence in a mouse model of cryptococcosis. Additionally, analysis of nutrient sensing functions for C. neoformans revealed regulatory connections between phosphate acquisition and storage and the iron regulator Cir1, cyclic AMP (cAMP)-dependent protein kinase A (PKA), and the calcium-calmodulin-activated protein phosphatase calcineurin. Deletion of the VTC4 gene encoding a polyphosphate polymerase blocked the ability of C. neoformans to produce polyphosphate. The vtc4 mutant behaved like the wild-type strain in interactions with macrophages and in the mouse infection model. However, the fungal load in the lungs was significantly increased in mice infected with vtc4 deletion mutants. In addition, the mutant was impaired in the ability to trigger blood coagulation in vitro, a trait associated with polyphosphate. Overall, this study reveals that phosphate uptake in C. neoformans is critical for virulence and that its regulation is integrated with key signaling pathways for nutrient sensing.

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Section: Discussionmentioning

confidence: 93%

“…A transport and receptor (transceptor) function for Pho84 has been described to occur in S. cerevisiae (17,51). In addition, Pho84 is involved in the activation of PKA in S. cerevisiae (52). PKA is a key nutrient sensing function in C. neoformans (42), and the cAMP signaling pathway has regulatory interactions with Cir1 (43).…”

Section: Figmentioning

confidence: 99%

Defects in Phosphate Acquisition and Storage Influence Virulence of Cryptococcus neoformans

et al. 2014

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“…2). For example, it has been shown that, after prolonged Pi starvation, the repletion of Pi to cells leads to degradation of the high-affinity phosphate transporter Pho84 via the activation of protein kinase A (PKA) (129–133), demonstrating a connection between the glucose and phosphate signaling pathways. These studies also support a role for Pho84 as a Pi transceptor, which can sense as well as transport Pi.…”

Section: Crosstalk Between Nad+ Metabolism and Nutrient/stress Senmentioning

confidence: 99%

Regulation of NAD+ metabolism, signaling and compartmentalization in the yeast Saccharomyces cerevisiae

Kato

Lin

2014

DNA Repair

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Pyridine nucleotides are essential coenzymes in many cellular redox reactions in all living systems. In addition to functioning as a redox carrier, NAD+ is also a required co-substrate for the conserved sirtuin deacetylases. Sirtuins regulate transcription, genome maintenance and metabolism and function as molecular links between cells and their environment. Maintaining NAD+ homeostasis is essential for proper cellular function and aberrant NAD+ metabolism has been implicated in a number of metabolic- and age-associated diseases. Recently, NAD+ metabolism has been linked to the phosphate-responsive signaling pathway (PHO pathway) in the budding yeast Saccharomyces cerevisiae. Activation of the PHO pathway is associated with the production and mobilization of the NAD+ metabolite nicotinamide riboside (NR), which is mediated in part by PHO-regulated nucleotidases. Cross-regulation between NAD+ metabolism and the PHO pathway has also been reported; however, detailed mechanisms remain to be elucidated. The PHO pathway also appears to modulate the activities of common downstream effectors of multiple nutrient-sensing pathways (Ras-PKA, TOR, Sch9/AKT). These signaling pathways were suggested to play a role in calorie restriction-mediated beneficial effects, which have also been linked to Sir2 function and NAD+ metabolism. Here, we discuss the interactions of these pathways and their potential roles in regulating NAD+ metabolism. In eukaryotic cells, intracellular compartmentalization facilitates the regulation of enzymatic functions and also concentrates or sequesters specific metabolites. Various NAD+-mediated cellular functions such as mitochondrial oxidative phosphorylation are compartmentalized. Therefore, we also discuss several key players functioning in mitochondrial, cytosolic and vacuolar compartmentalization of NAD+ intermediates, and their potential roles in NAD+ homeostasis. To date, it remains unclear how NAD+ and NAD+ intermediates shuttle between different cellular compartments. Together, these studies provide a molecular basis for how NAD+ homeostasis factors and the interacting signaling pathways confer metabolic flexibility and contribute to maintaining cell fitness and genome stability.

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“…For example, after prolonged Pi starvation, repletion of Pi to cells leads to PKA activation-dependent degradation of phosphate transporter, Pho84 (Giots et al, 2003; Mouillon et al, 2005; Lundh et al, 2009; Popova et al, 2010; Samyn et al, 2012). These studies support a role for Pho84 as a Pi transceptor, a sensor and transporter of Pi.…”

Section: Phosphate Sensing Pathwaymentioning

confidence: 99%

Less is more: Nutrient limitation induces cross-talk of nutrient sensing pathways with NAD+ homeostasis and contributes to longevity

Tsang

Lin

2015

Front. Biol.

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Nutrient sensing pathways and their regulation grant cells control over their metabolism and growth in response to changing nutrients. Factors that regulate nutrient sensing can also modulate longevity. Reduced activity of nutrient sensing pathways such as glucose-sensing PKA, nitrogen-sensing TOR and S6 kinase homolog Sch9 have been linked to increased life span in the yeast, Saccharomyces cerevisiae, and higher eukaryotes. Recently, reduced activity of amino acid sensing SPS pathway was also shown to increase yeast life span. Life span extension by reduced SPS activity requires enhanced NAD+ (nicotinamide adenine dinucleotide, oxidized form) and nicotinamide riboside (NR, a NAD+ precursor) homeostasis. Maintaining adequate NAD+ pools has been shown to play key roles in life span extension, but factors regulating NAD+ metabolism and homeostasis are not completely understood. Recently, NAD+ metabolism was also linked to the phosphate (Pi)-sensing PHO pathway in yeast. Canonical PHO activation requires Pi-starvation. Interestingly, NAD+ depletion without Pi-starvation was sufficient to induce PHO activation, increasing NR production and mobilization. Moreover, SPS signaling appears to function in parallel with PHO signaling components to regulate NR/NAD+ homeostasis. These studies suggest that NAD+ metabolism is likely controlled by and/or coordinated with multiple nutrient sensing pathways. Indeed, cross-regulation of PHO, PKA, TOR and Sch9 pathways was reported to potentially affect NAD+ metabolism; though detailed mechanisms remain unclear. This review discusses yeast longevity-related nutrient sensing pathways and possible mechanisms of life span extension, regulation of NAD+ homeostasis, and cross-talk among nutrient sensing pathways and NAD+ homeostasis.

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Mutational analysis of putative phosphate- and proton-binding sites in the Saccharomyces cerevisiae Pho84 phosphate:H+ transceptor and its effect on signalling to the PKA and PHO pathways

Cited by 52 publications

References 42 publications

Defects in Phosphate Acquisition and Storage Influence Virulence of Cryptococcus neoformans

Defects in Phosphate Acquisition and Storage Influence Virulence of Cryptococcus neoformans

Regulation of NAD+ metabolism, signaling and compartmentalization in the yeast Saccharomyces cerevisiae

Less is more: Nutrient limitation induces cross-talk of nutrient sensing pathways with NAD+ homeostasis and contributes to longevity

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