Biology subjects

Sertour, N.

Publications and source records attributed to Sertour, N..

3 recordsLinked to original sources

bioRxiv2026

Starve, stress, and mate: Activation of the CCAAT-Binding complex overrides sterility of mating-type heterozygous Candida albicans

Sexual reproduction in the human fungal pathogen Candida albicans is typically restricted by a strict genetic lock: the a1-2 repressor present in standard mating-type heterozygous (MTLa/) diploid strains, which actively represses mating competency. While severe environmental pressures are known to influence fungal development, the molecular mechanisms that allow cells to override this genetic sterility block remain poorly understood. Here, we identify the highly conserved CCAAT-binding complex (CBC) as the critical developmental hub that integrates environmental stress to unlock mating in heterozygous diploids. By combining proteomic mapping (ChIP-SICAP) and transcriptomics (RNA-Seq) to define the regulatory network of the core CBC subunit Hap5, we demonstrate that CBC hyperactivation completely overrides the a1-2 repressor. This activation triggers a robust white-to-opaque phenotypic switch and initiates a mating-competence program in MTLa/ strains genetically locked in a sterile state. Crucially, this developmental transition is antagonized by the iron-regulatory partner Hap43, but is strictly dependent on physical interaction at the chromatin level with Cap1, the master regulator of the oxidative stress response. Our findings reveal that the CBC and Cap1 couple metabolic starvation (glucose and iron limitation) and oxidative stress to a core reproductive program, providing a mechanistic basis for how C. albicans bypasses genetic constraints on sexual reproduction to generate genetic diversity under hostile host conditions.

microbiology↗

bioRxiv2025

Polygenetic Determinants of Azole Resistance, Tolerance, and Heteroresistance in Candida albicans

Azole antifungals are widely used to treat Candida infections, yet therapeutic failures are common. In addition to resistance, fungal populations can exhibit tolerance and heteroresistance, subpopulation-driven drug responses that can contribute to treatment failure. Here, we performed a genome-wide association study (GWAS) on 557 genetically diverse C. albicans isolates to identify genetic loci associated with fluconazole susceptibility, tolerance, and heteroresistance. We uncovered a complex, polygenic architecture underlying all three traits, involving novel loci linked to stress responses, cell cycle, and genome integrity. Notably, canonical resistance genes were absent from our top associations, reflecting either their low frequency or lineage specificity. Functional validation of several candidate genes confirmed distinct genetic determinants for each drug response. Heritability estimates and conditional analyses revealed that susceptibility and heteroresistance are governed by partially overlapping but largely independent loci, with some genetic variants displaying opposing effects on different traits. This limited overlap suggests that each phenotype represents a distinct evolutionary strategy for drug evasion, which may not be simultaneously addressed by a single therapeutic approach. Our findings underscore the polygenic nature of adaptation to antifungal drugs and expand our understanding of drug response mechanisms in C. albicans. SIGNIFICANCEDespite advances in antifungal therapies, treatment failures in Candida albicans infections remain common and poorly understood. Standard clinical diagnostic tools rely on susceptibility testing to predict treatment outcomes, yet many treatment-refractory infections are caused by strains that appear susceptible in laboratory tests. This study provides the first genome-wide dissection of three distinct drug responses - susceptibility, tolerance, and heteroresistance - across a global population of C. albicans isolates. By identifying novel genetic contributors beyond canonical resistance genes, our findings shift the current paradigm toward a more nuanced, polygenic model of antifungal adaptation. These results underscore the importance of integrating tolerance and heteroresistance into clinical and research frameworks and point to new molecular pathways that could be leveraged to enhance antifungal strategies.

microbiology↗

bioRxiv2023

Metabolic reprogramming during Candida albicans planktonic-biofilm transition is modulated by the ZCF15 and ZCF26 paralogs

Candida albicans is a commensal of the human microbiota that can form biofilms on implanted medical devices. These biofilms are tolerant to antifungals and to the host immune system. To identify novel genes modulating C. albicans biofilm formation, we performed a large-scale screen with 2454 C. albicans doxycycline-dependent overexpression strains and identified 16 genes whose overexpression significantly hampered biofilm formation. Among those, overexpression of the ZCF15 and ZCF26 paralogs that encode transcription factors and have orthologs only in biofilm-forming species of the Candida clade, caused impaired biofilm formation both in vitro and in vivo. Interestingly, overexpression of ZCF15 specifically impeded biofilm formation without any defect in hyphal growth. Transcript profiling, transcription factor binding, and phenotypic microarray analyses conducted upon overexpression of ZCF15 and ZCF26 demonstrated their direct role in reprogramming cellular metabolism by regulating glycolytic cycle and tricarboxylic acid cycle genes. Taken together, this study has identified a new set of biofilm regulators, including ZCF15 and ZCF26, that appear to control biofilm development through their specific role in metabolic remodeling.

microbiology↗