Epigenetic repression of IL-1β by C1QBP restricts Dectin-1-mediated host defense against murine invasive candidiasis

Abstract

Invasive candidiasis, predominantly caused by Candida albicans, threatens immunocompromised individuals with high mortality. Dendritic cell-derived interleukin-1β, orchestrated via Dectin-1-mediated β-glucan recognition, is central to antifungal defense. While the Dectin-1/Syk/CARD9 axis governing Il1b transcription is defined, the epigenetic regulatory mechanisms remain elusive. Here, we identify Complement C1q binding protein (C1QBP) as a critical negative regulator of Dectin-1-mediated interleukin-1β production. C1QBP sequesters phosphorylated protein kinase C δ in the cytoplasm, preventing its nuclear transport. Nuclear phosphorylated-PKCδ activates the RNF20/RNF40 ubiquitin ligase complex, which recruits the methyltransferase DOT1L to catalyze histone H3 lysine 79 trimethylation at the Il1b locus to promote its transcription. DC-specific C1QBP depletion enhances interleukin-1β secretion, amplifies protective T helper 17 cell responses, and improves host resistance to systemic C. albicans infection in mice. Collectively, our findings establish C1QBP as a key checkpoint in a PKCδ-dependent epigenetic pathway that constrains antifungal immunity, highlighting its therapeutic potential for invasive fungal diseases. Engagement of Dectin-1 on dendritic cells drives IL-1β production and is a critical component of the immune response to invasive candidiasis. Here the authors show epigenetic repression of IL-1β by a complement binding protein can restrain the dectin1 driven immune response in a murine model of invasive candidiasis.