Candida albicans is the most frequently encountered fungal pathogen in humans, capable of causing mucocutaneous and systemic infections in immunocompromised individuals. C. albicans virulence is influenced by multiple factors. Importantly, iron acquisition and avoidance of the immune oxidative burst are two critical barriers for survival in the host. Prior studies using whole genome microarray expression data indicated that the CCAAT-binding factor is involved in the regulation of iron uptake/utilization and the oxidative stress response. This study examines directly the role of the CCAAT-binding factor in regulating the expression of oxidative stress genes in response to iron availability. The CCAAT-binding factor is a heterooligomeric transcription factor previously shown to regulate genes involved in respiration and iron uptake/utilization in C. albicans. Since these pathways directly influence the level of free radicals, it seemed plausible the CCAAT-binding factor regulates genes necessary for the oxidative stress response. In this study, we show the CCAAT-binding factor is involved in regulating some oxidative stress genes in response to iron availability, including CAT1, SOD4, GRX5, and TRX1. We also show that CAT1 expression and catalase activity correlate with the survival of C. albicans to oxidative stress, providing a connection between iron obtainability and the oxidative stress response. We further explore the role of the various CCAAT-binding factor subunits in the formation of distinct protein complexes that modulate the transcription of CAT1 in response to iron. We find that Hap31 and Hap32 can compensate for each other in the formation of an active transcriptional complex; however, they play distinct roles in the oxidative stress response during iron limitation. Moreover, Hap43 was found to be solely responsible for the repression observed under iron deprivation.
RationalEndothelial damage plays a central role in acute lung injury, and regeneration of lung vascular endothelium is required for its resolution in preclinical models.ObjectivesWe sought to define the cellular and molecular mechanisms underlying lung microvascular regeneration in acute lung injury induced by lung endothelial cell ablation.MethodsTransgenic mice were created expressing endothelial-targeted human diphtheria toxin receptor. Changes in lung cell populations and gene expression profiles were determined using single-cell RNA sequencing of dissociated lung cells (10x Genomics) at baseline (day 0) and days 3, 5 and 7 days after lung endothelial cell ablation.Measurements and Main ResultsIntratracheal instillation of diphtheria toxin resulted in ablation of ∼70% of lung endothelial cells, producing severe acute lung injury, with complete resolution by 7 days. Single cell analysis revealed 8 distinct endothelial cell clusters, including type-A capillary endothelial cells which were characterized by the unique expression of apelin at baseline. Diphtheria toxin-induced ablation resulted in the emergence of novel stem-like endothelial cells in the transitional ‘general’ capillary type-B endothelial population at day 3, characterized by the de novo expression of apelin. This was followed by the appearance of proliferative endothelial cells at day 5 expressing apelin receptor and Forkhead box M1 which were responsible for replenishment of all depleted endothelial cell populations. Treatment with an apelin receptor antagonist prevented recovery post DT resulting in excessive mortality.ConclusionsTargeted endothelial cell ablation revealed a remarkable regenerative capacity of the lung microvasculature orchestrated by newly emergent apelin-expressing endothelial stem-like cells primed for endothelial repair.
p53 gene family members in humans and other organisms encode a large number of protein isoforms whose functions are largely undefined. Using Drosophila as a model, we find that a p53B isoform is expressed predominantly in the germline where it colocalizes with p53A into subnuclear bodies. It is only p53A, however, that mediates the apoptotic response to ionizing radiation in the germline and soma. In contrast, p53A and p53B are both required for the normal repair of meiotic DNA breaks, an activity that is more crucial when meiotic recombination is defective. We find that in oocytes with persistent DNA breaks p53A is also required to activate a meiotic pachytene checkpoint. Our findings indicate that Drosophila p53 isoforms have DNA lesion and cell type-specific functions, with parallels to the functions of mammalian p53 family members in the genotoxic stress response and oocyte quality control.
Abstractp53 gene family members in humans and other organisms encode a large number of protein isoforms whose functions are largely undefined. Using Drosophila as a model, we find that a p53B isoform is expressed predominantly in the germline where it colocalizes with p53A into subnuclear bodies. It is only p53A, however, that mediates the apoptotic response to ionizing radiation in the germline and soma. In contrast, p53A and p53B both respond to meiotic DNA breaks and are required during oogenesis to prevent persistent germline DNA breaks, an activity that is more crucial when meiotic recombination is defective. We find that in oocytes with persistent DNA breaks p53A is required to activate a meiotic pachytene checkpoint. Our findings indicate that Drosophila p53 isoforms have DNA lesion and cell type-specific functions, with parallels to the functions of mammalian p53 family members in the genotoxic stress response and oocyte quality control.
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