Complosome — the intracellular complement system

Abstract

The complement system is a recognized pillar of host defence against infection and noxious self-derived antigens. Complement is traditionally known as a serum-effective system, whereby the liver expresses and secretes most complement components, which participate in the detection of bloodborne pathogens and drive an inflammatory reaction to safely remove the microbial or antigenic threat. However, perturbations in normal complement function can cause severe disease and, for reasons that are currently not fully understood, the kidney is particularly vulnerable to dysregulated complement activity. Novel insights into complement biology have identified cell-autonomous and intracellularly active complement — the complosome — as an unexpected central orchestrator of normal cell physiology. For example, the complosome controls mitochondrial activity, glycolysis, oxidative phosphorylation, cell survival and gene regulation in innate and adaptive immune cells, and in non-immune cells, such as fibroblasts and endothelial and epithelial cells. These unanticipated complosome contributions to basic cell physiological pathways make it a novel and central player in the control of cell homeostasis and effector responses. This discovery, together with the realization that an increasing number of human diseases involve complement perturbations, has renewed interest in the complement system and its therapeutic targeting. Here, we summarize the current knowledge about the complosome across healthy cells and tissues, highlight contributions from dysregulated complosome activities to human disease and discuss potential therapeutic implications. Complement proteins and receptors with intracellular activity — the complosome — have emerged as important regulators of physiological processes. In this Review, the authors examine evidence of complosome activity across a variety of cells and tissues, as well as their contributions to human disease and therapeutic potential. Complement function is compartmentalized and operates systemically, locally in the extracellular space, and intracellularly within sub-cellular compartments and organelles. Intracellular complement — the complosome — serves non-classical roles as a novel central regulator of basic cell physiological processes including mitochondrial respiration, glycolysis, autophagy and gene transcription. The complosome functions across immune and non-immune cells and tissues where it controls normal cell turnover, the responses to infectious and non-infectious stimuli and the return to homeostasis. Perturbations in complosome activities contribute to human disease, including infections and infection-related pathological conditions, arthritic disease, atherosclerosis, cancer and kidney disease. Targeting the complosome, possibly in combination with the extracellularly active complement, might be therapeutically beneficial in complement-mediated pathological conditions. Complement function is compartmentalized and operates systemically, locally in the extracellular space, and intracellularly within sub-cellular compartments and organelles. Intracellular complement — the complosome — serves non-classical roles as a novel central regulator of basic cell physiological processes including mitochondrial respiration, glycolysis, autophagy and gene transcription. The complosome functions across immune and non-immune cells and tissues where it controls normal cell turnover, the responses to infectious and non-infectious stimuli and the return to homeostasis. Perturbations in complosome activities contribute to human disease, including infections and infection-related pathological conditions, arthritic disease, atherosclerosis, cancer and kidney disease. Targeting the complosome, possibly in combination with the extracellularly active complement, might be therapeutically beneficial in complement-mediated pathological conditions.