C1QBP interacts with Dectin-1 signaling to suppress IL-1ß via epigenetic silencing in Candida albicans infection
Dectin-1-mediated interleukin-1ß (IL-1ß) production is critical for antifungal immunity, yet the transcriptional regulation of IL-1ß during Candida albicans infection remain poorly defined. Here, we identify conventional type 2 dendritic cells (cDC2s) as the primary producers of IL-1ß 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-1ß production by sequestering phosphorylated PKCd (p-PKCd) in the cytosol, thereby preventing its nuclear translocation. Genetic ablation of C1qbp relieved this sequestration, enabling nuclear p-PKCd 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-1ß production, amplified protective TH17 responses, and significantly improved host resistance to disseminated candidiasis. Collectively, our findings reveal C1QBP as a spatial rheostat for p-PKCd that epigenetically silences Dectin-1-mediated inflammation, highlighting C1QBP as a therapeutic target to potentiate antifungal defense. Overall design: In this study, we identified a previously unrecognized role of C1QBP as a critical negative regulator of Dectin-1-mediated IL-1ß production in cDC2s during disseminated candidiasis. We demonstrated that C1QBP constrains antifungal immunity by sequestering phosphorylated PKCd in the cytoplasm, thereby preventing its nuclear translocation and subsequent epigenetic activation of the Il1b gene. Our findings reveal an intricate spatial and epigenetic regulatory circuit that fine-tunes inflammatory responses to fungal pathogens, positioning C1QBP as a potential therapeutic target for enhancing host defense against invasive fungal infections.