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.

Fig. 1. The complement system and its functional compartmentalization.

a, Circulating liver-produced complement can be activated through three pathways that result in the formation of C3 and C5 convertases, which cleavage-activate C3 into C3a and C3b, and C5 into C5a and C5b, respectively. This process leads to the formation of the membrane attack complex (MAC) and the induction of classical complement functions. Several regulators (in red) control complement activation. b, Systemic complement protects against bloodborne threats, whereas extra-hepatic cell-derived local complement activation, driven by C3 and C5 secreted by immune and non-immune cells (and subsequent extracellular formation of C3 and/or C5 convertase formation) supports cell survival and cell-specific effector responses in an autocrine and/or paracrine (not shown) manner. c, Activation of cell-autonomous, intracellular complement in immune and non-immune cells can occur at different subcellular locations. The generated activation fragments perform their activities across distinct cell sub-compartments and support normal physiological processes. CD46 is included because its cleaved intracellular domain is considered to be a member of the complosome. ATP prod., adenosine triphosphate production; C1-INH, C1 and MASP1/2 inhibitor; C3aR, C3a receptor; C4BP, C4b binding protein; C5aR, C5a receptor; CR1, complement receptor 1; ER, endoplasmic reticulum; ETC, electron transport chain; F, factor; MAC, membrane attack complex; MASP1/2, MBL serine proteases 1 and 2; MAVS, mitochondrial anti-viral signalling protein; MBL, mannose-binding lectin; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3 inflammasome; OXPHOS, oxidative phosphorylation; PW, pathways; ROS, reactive oxygen species. *Although hepatocytes are the principal source of secreted and circulating C3 and C5, they also engage cell-intrinsic intracellular C3 for homeostatic control of their lipid metabolism.

Fig. 2. Complosome across cells and tissues.

The figure illustrates the cells and tissues in which intracellular C3 or C5, or other complement components and receptors have been observed. The C3 and C5 activation fragments that drive the different cellular functions and biological pathways are not shown for simplicity and because they are not known in all cases. Cell-specific activities and overall contributions to normal tissue function of the complosome are shown to the right of each cell and tissue type. The blue arrow below indicates that tissue-resident immune cells (and their complosome) probably also participate in normal tissue homeostasis. C3aR, C3a receptor; C5aR1 or 2, C5a receptor 1 or 2; ETC, electron transport chain; FH, factor H; FHR-3, factor H-related protein 3; MAVS, mitochondrial anti-viral signalling protein; NF-κB, nuclear factor κB; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3 inflammasome; OXPHOS, oxidative phosphorylation; RIG-I, retinoic acid-inducible gene-I; ROS, reactive oxygen species; SLEC, short lived effector T cell; T_H1, T helper 1; VLDL, very low density lipoprotein.

Fig. 3. The complosome in human disease.

The figure shows disease states that are associated with pathological alterations in the expression levels or activity of specific intracellular complement components. Included in the lower right rectangle are additional pathological conditions in which complosome dysregulation might have a role, but for which solid evidence is still missing. AD, Alzheimer’s disease; AMD, age-related macular degeneration; C1qBP, C1q binding protein (also known as globular head C1q receptor, gC1qR); C5aR1, C5a receptor 1; COPD, chronic obstructive pulmonary disease; FH, factor H; FHR-3, factor H-related protein 3; IBD, inflammatory bowel disease; MS, multiple sclerosis; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SLE, systemic lupus erythematosus.