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 complo some 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. Nature Reviews Nephrology Review articlecontributions of the complosome to human disease, including kidney disease. Finally, we consider the therapeutic potential of targeting the complosome in complement-mediated pathologies and highlight key limitations and caveats of complosome-focused clinical approaches. Classical functions of systemic and local extracellular complementThe human complement system comprises >50 proteins that either circulate in blood (specifically, core components and some complement regulators) or lymph, or exist as cell membrane-bound proteins (regulators and receptors) 1,2 . C3 and C5 are major effector molecules that are mostly secreted by the liver in a pro-enzymatic form. Complement C3 and C5 activation is initiated when one or several activation pathways is triggered by pathogen-or damage-associated molecular patterns (Fig. 1a). This recognition leads to the formation of C3 and C5 convertases, which then cleavage-activate C3 into C3a and C3b, and C5 into C5a and C5b, respectively. C5b combines with serum C6-C9 to form the membrane attack complex (MAC), which induces direct lytic killing of pathogens or noxious target cells. C3b opsonizes microbes and noxious host cells, which induces scavenger cells to phagocytose and destroy C3b-tagged targets 1,2,15,16 . Receptors for the anaphylatoxins C3a and C5a -C3a receptor (C3aR) and C5aR1 and 2, respectively -are expressed b...

Selective refueling of CAR T cells using ADA1 and CD26 boosts antitumor immunity

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Functional Analysis of a Novel Complement C5a Receptor 1-Blocking Monoclonal Antibody

“…An obstacle in targeting intracellular C5aR1 is the necessity of the respective C5aR1 inhibitor to be able to traverse the cellular membrane efficiently. Recently, a particular small-molecule C5aR1 inhibitor has been reported to be able to diffuse through the cellular membrane and abrogate intracellular C5aR1 signaling [35]. Antibodies are more difficult to transport across cell membranes, which mostly requires additional cell treatment, physical delivery methods, and/or attachment of antibodies to other compounds for enhanced uptake [36].…”

From complement to complosome in non‐alcoholic fatty liver disease: When location matters

“…Emerging evidence indicates that complement activation and effector functions extend beyond the extracellular milieu, extending into the intracellular space. Detailed reviews of this intracellular complement system, termed the “complosome”, have been previously published, including recently 15–17 . Briefly, it represents a novel concept characterised by a complex protein assembly that operates intracellularly and interacts with internal danger detection and effector systems, such as inflammasomes and autophagosomes 125–127 .…”

“…Intriguingly, mounting evidence suggests that complement components could play a role as an immunometabolic factor in driving various pathological conditions, including NAFLD. Furthermore, the unveiling of novel facets of complement biology, including the complosome, has paved the way for broadening our insights into the canonical and non‐canonical roles of the complement system in physiology as well as pathobiology 15–17 . In this review, we highlight the current knowledge on the emerging roles of the classical complement systems and the complosome in NAFLD.…”