Biology subjects

Tebbji, F.

Publications and source records attributed to Tebbji, F..

9 recordsLinked to original sources

bioRxiv2026

A new fungal taurine biosynthetic pathway promotes metabolic fitness and virulence in Candida albicans

Taurine is an abundant sulfur-containing metabolite with diverse roles in cellular physiology across many organisms, yet its biosynthesis and biological functions remain largely unexplored in fungi. Here, we provide evidence for endogenous taurine production in the major human fungal pathogen Candida albicans and identify Csd1, a cysteine sulfinic acid decarboxylase (CSAD)-related protein, as a major determinant of this process. Loss of CSD1 nearly abolished intracellular taurine and caused extensive remodeling of sulfur metabolism, including cysteine accumulation and altered abundance of methionine-cycle metabolites. Consistent with these metabolic defects, csd1 cells exhibited impaired growth and increased sensitivity to cysteine, oxidative and osmotic stresses, elevated temperature, reactive sulfur species, and the antifungal drugs amphotericin B and caspofungin. Exogenous taurine selectively rescued a subset of these phenotypes, indicating that CSD1 loss causes both taurine-dependent and broader metabolic defects. Csd1 was also required for normal hyphal morphogenesis, and csd1 cells displayed markedly attenuated virulence in a Galleria mellonella systemic infection model. Comparative sequence analysis revealed conservation of key features of the pyridoxal 5'-phosphate-dependent catalytic machinery shared with mammalian and bacterial CSADs, together with divergence within the predicted substrate-recognition pocket. Our genetic data further suggest that taurine production in C. albicans differs from the canonical metazoan cysteine sulfinic acid pathway and may involve branched or redundant routes. Together, these findings establish endogenous taurine production as a new facet of fungal sulfur metabolism and identify Csd1-dependent metabolism as an important contributor to sulfur homeostasis, stress adaptation, morphogenesis, and pathogenic fitness in C. albicans.

microbiology↗

bioRxiv2026

Isw2-mediated chromatin remodeling governs antifungal tolerance and heteroresistance in Candida albicans

Antifungal tolerance, unlike resistance, allows cells to grow slowly at concentrations above the minimum inhibitory concentration. While resistance mechanisms are well characterized, the pathways underlying tolerance remain elusive. Here, we performed a genetic screen of a transcriptional factor mutant library to identify regulators of azole tolerance in Candida albicans. This screen uncovered Isw2, the catalytic subunit of the ISW2 ATP-dependent chromatin remodeling complex, as a negative regulator of azole tolerance. Integrating transcriptomics, Isw2 DNA-binding profiles, and nucleosome-occupancy analyses revealed that Isw2 maintains a repressive chromatin architecture at the CRZ1 promoter, limiting the nucleosome-depleted region and suppressing CRZ1 transcription. Isw2 also modulates fluconazole heteroresistance and amphotericin B sensitivity through Crz1. In addition, we identified the copper-responsive transcription factor Mac1 as a context-dependent regulator of azole tolerance, acting negatively under copper limitation but positively under copper-replete conditions. Together, these findings reveal unexpected roles for chromatin remodeling and copper homeostasis in antifungal tolerance.

microbiology↗

bioRxiv2025

Crosstalk between the Ino80 complex and TOR signaling drives fungal adaptation to hypoxia through chromatin remodeling

In the human host, the opportunistic yeast Candida albicans must adapts to niches that vary markedly in oxygen tension, ranging from the hypoxic gastrointestinal and vaginal tracts to more oxygen-rich niches such as the skin. Thriving across this spectrum requires the capacity to dynamically rewire core metabolic pathways in response to fluctuating oxygen levels. Yet, despite the central role of oxygen in shaping fungal metabolism and fitness, the genetic basis underlying hypoxic adaptation in C. albicans remains incompletely understood. Here, we performed a genetic screen to identify genes required for adaptation to hypoxia (5% O2). This comprehensive approach revealed numerous genes spanning diverse metabolic and stress-related functions that are essential for optimal growth under oxygen-limiting conditions. Notably, this study uncovers a previously unrecognized role for the TOR (Target of Rapamycin) signaling pathway and the chromatin-remodeling complex Ino80 in orchestrating the fungal adaptive response to hypoxia. Integration of ino80 mutant transcriptomic data with Ino80 DNA-binding and nucleosome-occupancy profiles under conditional INO80 depletion revealed that this chromatin remodeler regulates the cellular phosphate demand associated with hypoxic exposure. The similarity between chromatin accessibility changes following TOR1 and INO80 depletion further suggests that Ino80 acts in concert with the TOR pathway to support growth and maintain phosphate homeostasis under low-oxygen conditions. Collectively, these findings provide new insight into how nutrient and oxygen signaling converge on chromatin remodeling, offering a mechanistic framework for understanding the regulatory logic underlying hypoxic adaptation in pathogenic fungi. ImportanceCandida albicans is an opportunistic fungal pathogen that colonizes diverse host niches, many of which are oxygen-limited. Understanding how this organism adapts to hypoxia is critical for elucidating the mechanisms underpinning both commensalism and pathogenicity of this yeast. Here, we reveal that the TOR signaling pathway and the Ino80 chromatin-remodeling complex are key regulators of fungal growth under low-oxygen conditions. Our data show that Ino80 coordinates phosphate homeostasis during hypoxia and functions in concert with TOR to maintain chromatin accessibility and metabolic adaptation. Our results uncover how oxygen and nutrient cues converge on chromatin remodeling, providing a framework for understanding how C. albicans and other human-associated fungi modulate their physiology to thrive and evolve in diverse host environments.

microbiology↗

bioRxiv2025

Met32 governs transcriptional control of sulfur metabolic flexibility and resistance to reactive sulfur species in the human fungal pathogen Candida albicans

Although considerable advances have been made in understanding the metabolic machinery that enables bacteria to utilize sulfur sources, many aspects of this process remain understudied in fungi. To explore the genetic circuit by which the highly prevalent human opportunistic yeast Candida albicans controls sulfur utilization, we characterized the transcriptional landscape associated with sulfur starvation in this fungus. We identified many desulfonation enzymes that were differentially modulated and showed that Jlp12, a sulfonate/-ketoglutarate dioxygenase, was critical for the utilization of different sulfur sources found in many niches of the human host. We also uncovered that the Zinc-finger transcription factor Met32 acts as a master regulator, that modulates genes of sulfur utilization including Jlp12. Importantly, we found that C. albicans Met32 exclusively regulates sulfur utilization genes, while in the Saccharomyces cerevisiae lineage, it controls methionine biosynthesis. This work also identified Seo13 as the first major facilitator superfamily transporter in fungi that transports the alternative sulfur source glutathione, under the direct control of Met32. Furthermore, we showed that Met32 modulates C. albicans tolerance to sulfite excess by tuning the basal transcriptional level of the superoxide dismutase Sod1. This underscores the dual role of Met32 in the breakdown of sulfur-containing metabolites and the neutralization of the resulting reactive sulfur species (RSS). Our study delineates a new mechanism by which fungal pathogens utilize sulfur sources and neutralize RSS and underscores its importance in fungal fitness in vivo. ImportanceCandida albicans is the most prevalent fungal colonizer of humans and it is also the first cause of disseminated fungal infections leading to a high mortality rate. The ability of this yeast to metabolize a plethora of carbon and nitrogen sources inside the host is a critical asset for both the commensal and the pathogenic lifestyles of this yeast. Thus, these pathways represent attractive targets for antifungal therapy. While sulfur is an essential nutritional element for all living organisms, its contribution to fungal virulence remains understudied. Here, we describe new players of sulfur utilization metabolism in C. albicans and underline their importance in supporting fungal virulence. This work emphasizes the significance of targeting sulfur metabolic flexibility to manage fungal infections.

microbiology↗

bioRxiv2023

Manganese homeostasis modulates fungal virulence and stress tolerance in Candida albicans

Due to the scarcity of transition metals within the human host, fungal pathogens have evolved sophisticated mechanisms to uptake and utilize these micronutrients at the infection interface. While considerable attention was turned to iron and copper acquisition mechanisms and their importance in fungal fitness, less was done regarding either the role of manganese (Mn) in infectious processes or the cellular mechanism by which fungal cells achieve their Mn- homeostasis. Here, we undertook transcriptional profiling in the pathogenic fungus Candida albicans experiencing both Mn starvation and excess to capture biological processes that are modulated by this metal. We uncovered that Mn scarcity influences diverse processes associated with fungal fitness including invasion of host cells and antifungal sensitivity. We show that Mn levels influence the abundance of iron and zinc emphasizing the complex crosstalk between metals. Deletion of SMF12, a member of Mn Nramp transporters confirmed its contribution to Mn uptake. smf12 was unable to form hyphae and damage host cells and exhibited sensitivity to azoles. We found that the unfolded protein response (UPR), likely activated by decreased glycosylation under Mn limitation, was required to restore growth when cells were shifted from a Mn-starved to a Mn-repleted medium. RNA-seq profiling of cells exposed to Mn excess revealed that UPR was also activated. Furthermore, the UPR signaling axis Ire1-Hac1 was required to bypass Mn toxicity. Collectively, this study underscores the importance of Mn homeostasis in fungal virulence, and comprehensively provides a portrait of biological functions that are modulated by Mn in a fungal pathogen.

microbiology↗

bioRxiv2021

Transcriptional control of hypoxic hyphal growth in the fungal pathogen Candida albicans

BackgroundThe ability of Candida albicans, an important human fungal pathogen, to develop filamentous forms is a crucial determinant for host invasion and virulence. Filamentation is triggered by different host environmental cues. Hypoxia, the dominant conditions that C. albicans encounters inside the human host, promote filamentation, however, the contributing mechanisms remain poorly characterized. MethodsWe performed a quantitative analysis of gene deletion mutants from different collections of protein kinases and transcriptional regulators in C. albicans to identify specific modulators of the hypoxic filamentation. We used genome-wide transcriptional profiling (Microarrays) and promoter occupancy (ChIP-chip) to characterize regulons of two transcription factors that were associated with the hypoxic filamentation. Genetic interactions were also used to assess functional relationships among the newly identified modulators of hypoxic filamentation and the well-known C. albicans core morphogenetic regulators. ResultsOur genetic screen uncovered two transcription factors, Ahr1 and Tye7, that act as prominent regulators of C. albicans filamentation specifically under hypoxia. Both ahr1 and tye7 mutants exhibited a hyperfilamentous phenotype specifically under an oxygen-depleted environment suggesting that these transcription factors act as negative regulators of hypoxic filamentation. By combining microarray and ChIP-chip data, we have characterized the set of genes that are directly modulated by Ahr1 and Tye7. We found that both Ahr1 and Tye7 modulate a different set of genes and biological processes. Our genetic epistasis analysis supports our genomic finding and suggests that Ahr1 and Tye7 act independently to modulate hyphal growth in response to hypoxia. Furthermore, our genetic interaction experiments uncovered that Ahr1 and Tye7 repress the hypoxic filamentation growth via the Efg1 and Ras1/Cyr1 pathways, respectively. ConclusionIn sum, this investigation represents an informative resource toward the understanding of how hypoxia, the predominant condition inside the host, shapes the invasive filamentous growth of C. albicans.

microbiology↗

bioRxiv2020

High resolution genome-wide occupancy in Candida spp. using ChEC-seq

To persist in their hostile and dynamic human host environments, fungal pathogens has to sense and adapt by modulating their gene expression to fulfil their cellular needs. Understanding transcriptional regulation on a global scale would uncover cellular processes linked to persistence and virulence mechanisms that could be targeted for antifungal therapeutics. Infections associated with the yeast Candida albicans, a highly prevalent fungal pathogen, and the multi-resistant related species C. auris are becoming a serious public health threat. To define the set of a gene regulated by a transcriptional regulator in C. albicans, Chromatin Immuno-Precipitation (ChIP) based techniques including ChIP-chip or ChIP-seq has been widely used. Here, we describe a new set of PCR-based MNase-tagging plasmids for C. albicans and other Candida spp. to determine genome-wide location of any transcriptional regulator of interest using Chromatin endogenous cleavage (ChEC) coupled to high-throughput sequencing (ChEC-seq). The ChEC procedure does not require protein-DNA crosslinking or sonication avoiding thus artefacts related to epitope masking or the hyper-ChIPable euchromatic phenomenon. In a proof-of-concept application of ChEC-seq, we provided a high-resolution binding map of the SWI/SNF chromatin remodeling complex, a master regulator of fungal fitness in C. albicans in addition to the transcription factor NsiI that is an ortholog of the DNA-binding protein Reb1 for which genome-wide occupancy were previously established in Saccharomyces cerevisiae. The ChEC-seq procedure described here will allow a high-resolution genomic location definition which will enable a better understanding of transcriptional regulatory circuits that govern fungal fitness and drug resistance in these medically important fungi. ImportanceSystemic fungal infections caused by Candida albicans and the superbug C. auris are becoming a serious public health threat. The ability of these yeasts to cause disease is linked to their faculty to modulate the expression of genes that mediate their escape from the immune surveillance and their persistence in the different unfavourable niches within the host. Comprehensive knowledge on gene expression control of fungal fitness is consequently an interesting framework for the identification of essential infection processes that could be hindered by chemicals as potential therapeutics. Here, we expanded the use of ChEC-seq, a technique that was initially developed in the yeast model Saccharomyces cerevisiae to identify genes that are modulated by a transcriptional regulator, to the pathogenic yeasts C. albicans and C. auris. This robust technique will allow a better characterization of key gene expression regulators and their contribution to virulence and antifungal resistance in these pathogenic yeasts.

genomics↗

bioRxiv2020

Transcriptome analysis uncovers a link between copper metabolism, and both fungal fitness and antifungal sensitivity in the opportunistic yeast Candida albicans

Copper homeostasis is an important determinant for virulence of many human pathogenic fungi such as the highly prevalent yeast Candida albicans. However, beyond the copper transporter Ctr1, little is known regarding other genes and biological processes that are affected by copper. To gain insight into the cellular processes that are modulated by copper abundance in C. albicans, we monitored the global gene expression dynamic under both copper depletion and excess using RNA-seq. Beyond copper metabolism, other different transcriptional programs related to fungal fitness such as stress responses, antifungal sensitivity, host invasion and commensalism were modulated in response to copper variations. We have also investigated the transcriptome of the mutant of the copper utilization regulator, mac1, and identified potential direct targets of this transcription factor under copper starvation. We also showed that Mac1 was required for the invasion and adhesion to host cells and antifungal tolerance. This study provides a framework for future studies to examine the link between copper metabolism and essential functions that modulate fungal virulence and fitness inside the host.

microbiology↗

bioRxiv2016

A systematic cell size screen uncovers coupling of growth to division by the p38/HOG network in Candida albicans

Cell size is a complex trait that responds to developmental and environmental cues. Quantitative analysis of the size phenome in the pathogenic yeast Candida albicans uncovered 195 genes that markedly altered cell size, few of which overlapped with known size genes in other yeast species. A potent size regulator specific to C. albicans was the conserved p38/HOG MAPK module that mediates the osmotic stress response. Basal HOG activity inhibited the SBF G1/S transcription factor complex in a stress-independent fashion to delay the G1/S transition. The HOG network also governed ribosome biogenesis through the master transcriptional regulator Sfp1. Hog1 bound to the promoters and cognate transcription factors for both the G1/S and ribosome biogenesis regulons and thereby directly linked cell growth and division. These results illuminate the evolutionary plasticity of size control and identify the HOG module as a nexus of cell cycle and growth regulation.

cell biology↗