The secret life of complement: challenges and opportunities in exploring functions of the complosome in disease

Abstract

The complement system is a highly conserved and essential immune component with pivotal roles in innate and adaptive immunity. It is increasingly recognized that the complement system has a profound impact on disease. Current complement-targeting therapeutics for clinical use almost exclusively target the complement system in circulation. However, recent discoveries have demonstrated that complement is not only liver derived and plasma operative, but also synthesized and activated inside many cells locally within tissues, performing noncanonical, cell-autonomous intracellular functions, collectively referred to as the complosome. These intracellular complement pathways are distinct from the classical plasma-based system and critical for regulating fundamental cellular processes, including metabolism, gene transcription, autophagy, and the activation and resolution of inflammation. This Review explores the emerging roles of the complosome and current knowledge regarding its relation to human diseases, highlighting evidence across organ systems and disease states, including the kidneys, digestive tract, lungs, heart, CNS, musculoskeletal system, skin, and cancer. We also review current scientific approaches for detecting and functionally investigating the complosome, addressing challenges such as technological limitations and the need for advanced experimental models to delineate its tissue-specific roles. Finally, we discuss central unanswered questions critical for developing innovative therapeutic strategies targeting intracellular complement pathways. These strategies hold potential to modulate disease-specific mechanisms while preserving systemic complement activity.

Figure 1. Canonical pathways of complement activation and regulation in circulation.

Three principal pathways, the classical, lectin, and alternative, can initiate complement activation upon detection of specific triggers, leading to proteolytic processing of the central components C3 and C5 by their respective multimeric convertases. The generated fragments, alongside formation of the membrane attack complex (MAC), serve as effector molecules (solid red) that clear danger signals through opsonization, complement receptor binding, or direct cell lysis. Multiple regulators (blue) act at several points in the cascade to prevent unintended, prolonged, or excessive activation. Additional serum proteases, including thrombin, which can also activate complement, are not depicted (see Figure 2). MBL mannose-binding lectin; MASPs, mannose-binding lectin serine proteases; FB, factor B; FD, factor D; FP, properdin; C1inh, C1 inhibitor; C4BP, C4b-binding protein; CR1, complement receptor 1; CP, carboxypeptidase; CLU, clusterin.

Figure 2. Schematic overview of complosome biology.

(A) Intracellular complement can originate from de novo gene transcription by cells, uptake from plasma, cointernalization with opsonized pathogens, or from intracellular stores in subcellular organelles. (B) C3 activation proceeds via canonical convertases (see Figure 1) or through nonconvertase-dependent proteolysis. Mechanisms shown in boxes have been demonstrated to function intracellularly. By contrast, how C5 becomes activated inside cells remains poorly characterized. (C) Complosome functions are illustrated, grouped by protein-protein interactions (top right), receptor-ligand-dependent interactions (left), and DNA-binding mechanisms (bottom right). IL-1β mat., Il-1b maturation.

Figure 3. Overview of the complosome in human disease.

Diseases are grouped by organ system, with local complement dysregulation listed in black text and complosome-related dysregulation in red text. Daggers denote disorders that rely primarily on model system data. Asterisks denote conditions for which local complement involvement is hypothesized but not definitively proven.