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C1QBP interacts with Dectin-1 signaling to suppress IL-1β via epigenetic silencing in Candida albicans infection

ABSTRACT: Dectin-1-mediated interleukin-1β (IL-1β) production is critical for antifungal immunity, yet the transcriptional regulation of IL-1β during Candida albicans infection remain poorly defined. Here, we identify conventional type 2 dendritic cells (cDC2s) as the primary producers of IL-1β in the kidney during disseminated candidiasis and uncover Complement C1q binding protein (C1QBP; gC1qR/p32) as a key transcriptional repressor. Mechanistically, C1QBP constrains Dectin-1-driven IL-1β production by sequestering phosphorylated PKCδ (p-PKCδ) in the cytosol, thereby preventing its nuclear translocation. Genetic ablation of C1qbp relieved this sequestration, enabling nuclear p-PKCδ to directly activate the E3 ubiquitin ligase complex RNF20/RNF40. This complex in turn facilitated DOT1L-mediated histone H3 lysine 79 trimethylation (H3K79me3) across the Il1b gene body, epigenetically enhancing its transcription. Consequently, DC-specific C1QBP depletion elevated IL-1β production, amplified protective TH17 responses, and significantly improved host resistance to disseminated candidiasis. Collectively, our findings reveal C1QBP as a spatial rheostat for p-PKCδ that epigenetically silences Dectin-1-mediated inflammation, highlighting C1QBP as a therapeutic target to potentiate antifungal defense.

ORGANISM(S): Mus musculus

PROVIDER: GSE313539 | GEO | 2026/01/31

REPOSITORIES: GEO

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Project description:Candida albicans is the major invasive fungal pathogen of humans, causing diseases ranging from superficial mucosal infections to disseminated, systemic infections which are often life threatening. Hematogenously disseminated candidiasis (HDC) has a 47% mortality rate despite current antifungal therapy. An increase in prevalence, as well as an increasing resistance to most of the clinically important antifungal therapies, provides a strong impetus to understand the molecular mechanisms of pathogenesis and the acquisition of drug resistance. This information holds promise to identify novel therapeutic targets. A complete and accurate characterization of how the transcriptome of C. albicans responds to its interaction with cells from the host is an absolute necessity to accomplish this goal. RNA-seq (deep-sequencing of cDNA) provides an unbiased method to define comprehensively and systematically the transcriptome of an organism. We propose a comprehensive characterization of the C. albicans transcriptome in two different human tissue culture models, using RNA-seq. Such a characterization will shed unprecedented light on how fungal pathogens sense and respond to the host environment and how the host tissue responds to fungal invasion. We performed a comprehensive characterization of the C. albicans transcriptome in two different murine models of candidiasis (HDC and oropharyngeal candidiasis (OPC)), and two different human tissue culture models, using RNA-seq. Because the two murine models accurately recapitulate the pathology that is observed in clinical cases of candidiasis, we are confident that gene expression levels will provide an accurate representation of what occurs during the course of an infection in humans. Such a characterization of the in vivo transcriptome will shed unprecedented light on how fungal pathogens sense and respond to the host environment and how the host tissue responds to fungal invasion. PRJNA211732 C. albicans strain SC5314 was used to infect mice in a murine model of systemic candidiasis as well as a murine model of oropharyngeal candidiasis. For the disseminated model, kidneys were harvested at 6 hours, 12 hours, 24 hours and 48 hours after infection. For the oropharyngeal model, tongues were harvest at 1 day, 2 days, 3 days, and 5 days after infection. Total RNA was extracted from all harvested tissues and subject to RNA-seq. We also tested 3 C. albicans mutants in the disseminated model. For the infections with the mutant strains, only 1 timepoint (24 hours post-infection) was analyzed.

Project description:Candida albicans is the major invasive fungal pathogen of humans, causing diseases ranging from superficial mucosal infections to disseminated, systemic infections which are often life threatening. Hematogenously disseminated candidiasis (HDC) has a 47% mortality rate despite current antifungal therapy. An increase in prevalence, as well as an increasing resistance to most of the clinically important antifungal therapies, provides a strong impetus to understand the molecular mechanisms of pathogenesis and the acquisition of drug resistance. This information holds promise to identify novel therapeutic targets. A complete and accurate characterization of how the transcriptome of C. albicans responds to its interaction with cells from the host is an absolute necessity to accomplish this goal. RNA-seq (deep-sequencing of cDNA) provides an unbiased method to define comprehensively and systematically the transcriptome of an organism. We propose a comprehensive characterization of the C. albicans transcriptome in two different human tissue culture models, using RNA-seq. Such a characterization will shed unprecedented light on how fungal pathogens sense and respond to the host environment and how the host tissue responds to fungal invasion. We performed a comprehensive characterization of the C. albicans transcriptome in two different murine models of candidiasis (HDC and oropharyngeal candidiasis (OPC)), and two different human tissue culture models, using RNA-seq. Because the two murine models accurately recapitulate the pathology that is observed in clinical cases of candidiasis, we are confident that gene expression levels will provide an accurate representation of what occurs during the course of an infection in humans. Such a characterization of the in vivo transcriptome will shed unprecedented light on how fungal pathogens sense and respond to the host environment and how the host tissue responds to fungal invasion. PRJNA86065 Two different strains of C. albicans (SC5314 or WO-1) were used to infect two different types of human tissue culture monolayers (HUVECs or OKF6-TERT2). RNA from the infection mixtures were harvested at 90 minutes, 5 hours and 8 hours post infection. Experiments were performed in biological duplicate.

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C1QBP interacts with Dectin-1 signaling to suppress IL-1β via epigenetic silencing in Candida albicans infection

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