Intracellular C3 regulates the immune response to infection via NF-κB signaling.

Complement factor C3 is one of the most abundant proteins in the bloodstream and a central part of the complement system. Upon activation, C3 facilitates bacterial recognition and clearance in the extracellular environment. Initially regarded as a serum effector component, C3 is also emerging as an intracellular protein regulating basic cellular processes. Previously, we reported that intracellular, cytosolic C3 can opsonize bacteria and impact their virulence. In this study, we show that cells lacking C3 exhibit altered gene expression that influences immune responses to infection and inflammation. We observed decreased cytokine secretion in C3-deficient cells, which was rescued by expression of non-canonical, cytosolic C3. Further investigation revealed that C3 deficiency impairs signal transduction within the NF-κB signaling pathway, which is attributed to decreased expression of Toll-like receptors. This effect is reversed in cells expressing cytosolic C3, where receptor expression and pathway activation are restored. Therefore, we propose a novel role of intracellular, cytosolic C3 in shaping immune responses by modulating the expression of receptors critical to pathogen recognition.