Inside job: Roles of intracellular C3

Our understanding of the complement system continues to grow beyond that of a liver-derived systemically operative mechanism of pathogen clearance to a central orchestrator of single-cell behavior and tissue biology. These expanded activities reflect the extrahepatic and local production of complement by many, if not most, cells, and the unexpected recent finding that complement also serves important physiological intracellular roles. The complement core component C3 has emerged as a particularly critical player in basic cell functions. Here, we provide an overview of the currently known forms and functions of intracellular C3 and the mechanisms that control it. We also discuss 2 emerging concepts as potential key areas for future exploration: intracellular C3 as a second layer of pathogen defense at host-environmental interfaces and "C3 licensing." We conclude by suggesting that the potential clinical implications surrounding perturbations in intracellular C3 activities should be explored better.