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Complosome — the intracellular complement system

Nature Reviews Nephrology volume 19, pages 426–439 (2023)Cite this article

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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.

Key points

  • 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.

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Fig. 1: The complement system and its functional compartmentalization.
Fig. 2: Complosome across cells and tissues.
Fig. 3: The complosome in human disease.

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Acknowledgements

Work in the Kemper laboratory is supported in part by the Intramural Research Program of the National Institutes of Health, National Heart, Lung, and Blood Institute (ZIA/hl006223 to C.K.).

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  1. National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Complement and Inflammation Research Section (CIRS), Bethesda, MD, USA

    Erin E. West & Claudia Kemper

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All authors researched data for the article, made substantial contributions to discussions of the content and wrote, reviewed or edited the manuscript before submission.

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Correspondence to Claudia Kemper.

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Nature Reviews Nephrology thanks M. Bosmann, P. Cravedi, A. Jayaraman, L. Roumenina and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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West, E.E., Kemper, C. Complosome — the intracellular complement system. Nat Rev Nephrol 19, 426–439 (2023). https://doi.org/10.1038/s41581-023-00704-1

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