Biology subjects

Casal, M.

Publications and source records attributed to Casal, M..

6 recordsLinked to original sources

bioRxiv2025

The ATO gene family governs Candida albicans colonisation in the dysbiotic gastrointestinal tract

The fungal pathogen Candida albicans colonises the human gut where short-chain fatty acids (SCFAs) offer sources of carbon. This fungus harbours one of the largest microbial families of ATO (Acetate Transport Ortholog) genes, which encode putative SCFA transport proteins. Here, we generate C. albicans null mutants lacking individual or all known putative SCFA transporter genes and compare their phenotypes in vitro and in vivo. We show that blocking ATO function in C. albicans impairs SCFA uptake and growth, particularly on acetate. The uptake of acetate is largely dependent on a functional Ato1 (also known as Frp3/Ato3) and it is effectively abolished upon deletion of all ATO genes. We further demonstrate that deletion of the entire ATO gene family, but not inactivation of ATO1 alone, compromises the stable colonisation of C. albicans in the murine gastrointestinal tract following bacterial disruption by broad-spectrum antibiotics. Our data suggest that the ATO gene family has expanded and diversified during the evolution of C. albicans to promote the fitness of this fungal commensal during gut colonisation, in part through SCFA utilisation. IMPORTANCEThe human gut is rich in microbial fermentation products such as SCFAs, which serve as key nutrients for both bacteria and fungi. C. albicans, a common fungal resident of the gut and a cause of opportunistic infections, carries an unusually large family of ATO genes. This study reveals that this ATO gene family is required for the efficient uptake of acetate, the most abundant SCFA in the gut, and for stable colonisation of the gut. These findings uncover a new layer of metabolic adaptation in fungal commensals of humans and suggest that transporter gene expansion can shape microbial fitness in response to environmental nutrient signals.

microbiology↗

bioRxiv2025

Lactic acid influences iron assimilation by a fungal pathogen via the iron reductive uptake pathway

Candida albicans is a fungal commensal of humans that often causes mucosal infections in otherwise healthy individuals, and also serious infections in immunocompromised patients. The capacity of this fungus to colonise and cause disease relies on its ability to grow within the host, adapting to various nutrient restrictions and physicochemical conditions. The presence of alternative carbon sources, such as the lactate produced by the local microbiota, influences C. albicans antifungal drug resistance and immune evasion. In this study, we used genome-wide transcriptomic analysis to investigate the effect of lactate exposure upon metabolic rewiring. We provide evidence that C. albicans cells respond to growth in the presence of lactate at pH 5 by regulating genes encoding micronutrient transporters, notably iron transporters. More specifically, lactate triggers the downregulation of genes on the reductive iron uptake pathway, inferring a diminished requirement for high-affinity iron uptake. This is supported by the observation that lactate promotes the intracellular accumulation of iron by C. albicans cells. Lactate even enhances the growth of iron-transport defective C. albicans cells under iron-limited conditions. Lactate is known to activate protein kinase A (PKA) signalling. However, lactate-induced iron assimilation is PKA-independent. This work provides new insights into the role of lactate in iron homeostasis - two important factors that promote C. albicans virulence in the mammalian host, where nutritional immunity is a key antimicrobial strategy. ImportanceCandida albicans is a major opportunistic fungal pathogen capable of causing life- threatening infections, particularly in immunocompromised individuals. Its ability to adapt to diverse host environments underlies its success as a commensal and pathogen. This study provides new insights into the metabolic flexibility of C. albicans, with a specific focus on how lactate, a common carbon source in host niches, influences iron acquisition and homeostasis. Our findings reveal that, during growth at pH 5, lactate modulates the expression of micronutrient transporters and enhances iron assimilation in C. albicans. These results suggest a role of lactate in promoting iron uptake, potentially facilitating fungal colonization and persistence within the host. By elucidating the molecular and phenotypic consequences of lactate exposure upon iron metabolism, this study contributes to a deeper understanding of host-pathogen interactions.

cell biology↗

bioRxiv2025

Expansion, functional diversification and gene fusion events in the Ato protein family

Candida albicans, a commensal opportunistic pathogen, exhibits remarkable metabolic flexibility and adaptability to environmental changes. In glucose-limited niches, it utilizes alternative carbon sources such as carboxylic acids, which may influence its pathogenicity. In Saccharomyces cerevisiae, the uptake of monocarboxylates occurs through regulated plasma membrane (PM) transport proteins, such as Ato1 (Ady2), which belongs to the Acetate Uptake Transporter (AceTr) family. In C. albicans, these proteins are notably expanded, consisting of ten Ato-like proteins (ATO1-ATO10), whose functions remain unknown. Here, we investigated the role of Ato proteins in carboxylic acid utilization by C. albicans using in-silico and functional analysis. Our data revealed that several C. albicans Atos retain conserved AceTr motifs but possess distinct structural features, including differences in pore radius and binding sites for acetate and lactate. Expression analysis revealed that Ato1, Ato2, Ato3, and Ato6 exhibit distinct cellular localization and expression levels on the plasma membrane, depending on the presence or absence of monocarboxylates. Remarkably, deletion of ATO1 impaired Ato2 and Ato3 expression and caused ER retention of a distinct form of Ato2, suggesting a central regulatory role for Ato1 in the Ato transport system. Finally, we identified a novel Ato-related protein family in vertebrates. This family has three consecutive 6-helix transport domains and a unique C-terminal fusion with Sua5/YciO/YrdC, an enzyme involved in tRNA modification. Overall, our data suggests that the Ato protein family might play a critical role in the utilization of acetic or lactic acids in C. albicans. It also proposes potential functional redundancy among its members, which may contribute to rapid environmental adaptation and pathogenicity.

microbiology↗

bioRxiv2024

Endocytosis of the plasma membrane carboxylate transporter Jen1 in Saccharomyces cerevisiae under alkali stress: a mechanism for preventing loss of essential metabolites

In batch cultures of Saccharomyces cerevisiae grown on lactate, medium alkalinization coincides with endocytosis of the Jen1 lactate/pyruvate transporter. To assess how culture pH impacts Jen1 endocytosis, S. cerevisiae was grown in carbon-limited continuous cultures with a mixed ethanol-lactate feed. When applying a linearly increasing pH (6.75 to 7.25), extracellular lactate and pyruvate concentrations increased progressively. Up to pH 7.0, these concentrations aligned with the thermodynamic equilibrium of Jen1-mediated electroneutral carboxylate-proton symport, while Jen1 internalization became more pronounced above pH 7.0. Transcriptional upregulation of genes involved in oxidative phosphorylation, together with higher residual lactate levels, indicated increased energy demands at supra-optimal pH values. By analyzing transport, endocytosis, and transcriptional responses in actively growing continuous cultures, this study uncovers pH-dependent physiological challenges associated with electroneutral carboxylate/proton symport. The data support the hypothesis that Jen1 internalization evolved to prevent intracellular metabolite loss under unfavorable pH conditions. These findings provide novel insights into the physiological consequences of transporter energy coupling and the ecophysiological relevance of anion transporters when extracellular pH approaches or exceeds cytosolic pH.

microbiology↗

bioRxiv2022

NIT: an open-source tool for information theoretic analysis of neural population data

Information theory provides a popular and principled framework for the analysis of neural data. It allows to uncover in an assumption-free way how neurons encode and transmit information, capturing both linear and non-linear coding mechanisms and including the information carried by interactions of any order. To facilitate its application, here we present Neuroscience Information Toolbox (NIT), a new toolbox for the accurate information theoretical analysis of neural data. NIT contains widely used tools such as limited sampling bias corrections and discretization of neural probabilities for the calculation of stimulus coding in low-dimensional representation of neural activity (e.g. Local Field Potentials or the activity of small neural population).Importantly, it adds a range of recent tools for quantifying information encoding by large populations of neurons or brain areas, for the directed transmission of information between neurons or areas, and for the calculation of Partial Information Decompositions to quantify the behavioral relevance of neural information and the synergy and redundancy among neurons and brain areas. Further, because information theoretic algorithms have been previously validated mainly with electrophysiological recordings, here we used realistic simulations and analysis of real data to study how to optimally apply information theory to the analysis of two-photon calcium imaging data, which are particularly challenging due to their lower signal-to-noise and temporal resolution. We also included algorithms (based on parametric and non-parametric copulas) to compute robustly information specifically with analog signals such as calcium traces. We provide indications on how to best process calcium imaging traces and to apply NIT depending on the type of calcium indicator, imaging frame rate and firing rate levels. In sum, NIT provides a toolbox for the comprehensive and effective information theoretic analysis of all kinds of neural data, including calcium imaging.

neuroscience↗

bioRxiv2021

Interactions of cytosolic termini of the Jen1 monocarboxylate transporter are critical for trafficking, transport activity and endocytosis

Plasma membrane (PM) transporters of the major facilitator superfamily (MFS) are essential for cell metabolism and growth, as well as for survival in response to stress or cytotoxic drugs, in both prokaryotes and eukaryotes. In the yeast Saccharomyces cerevisiae, Jen1 is a monocarboxylate/H+ symporter that has been used to dissect the molecular details underlying control of cellular expression, transport mechanism and turnover of MFS transporters. Here, we present evidence supporting previously non-described roles of the cytosolic N- and C- termini in Jen1 biogenesis, PM stability and activity, through functional analyses of rationally designed truncations and chimeric constructs with UapA, a S. cerevisiae endocytosis-insensitive purine transporter from Aspergillus nidulans. Our results reveal a cryptic role of the N-terminal region and thus show that both cytosolic N- and C-termini are critical for Jen1 trafficking to the PM, transport activity and endocytosis. In particular, we provide evidence that the N- and the C-cytosolic termini of Jen1 undergo transport-dependent dynamic intra-molecular interactions, which critically affect the mechanism of transport and turnover of Jen1. Our results support an emerging concept where the cytosolic tails of PM transporters control transporter expression and function, through flexible intra-molecular interactions with each other and the transmembrane core of the protein. This idea may be extended to other MFS members providing a deeper understanding of conserved, but also evolving, mechanisms underlying MFS transporter structure-function relationships.

microbiology↗