Complement, complosome, and complotype: A perspective

Abstract

Recent rapid progress in key technological advances, including the broader accessibility of single‐cell “omic” approaches, have allowed immunologists to gain important novel insights into the contributions of individual immune cells in protective immunity and immunopathologies. These insights also taught us that there is still much to uncover about the (cellular) networks underlying immune responses. For example, in the last decade, studies on a key component of innate immunity, the complement system, have defined intracellularly active complement (the complosome) as a key orchestrator of normal cell physiology. This added an unexpected facet to the biology of complement, which was long considered fully explored. Here, we will summarize succinctly the known activation modes and functions of the complosome and provide a perspective on the origins of intracellular complement. We will also make a case for extending assessments of the complotype, the individual inherited landscape of common variants in complement genes, to the complosome, and for reassessing patients with known serum complement deficiencies for complosome perturbations. Finally, we will discuss where we see current opportunities and hurdles for dissecting the compartmentalization of complement activities toward a better understanding of their contributions to cellular function in health and disease.

Complement System and the Kidney: Its Role in Renal Diseases, Kidney Transplantation and Renal Cell Carcinoma

“…Core complement proteins C3 and C5, their activation fragments, their receptors, and their regulators have been found to be active intracellularly as the complosome [46][47][48]. Complosome components not only interact with each other but also with intracellular danger sensor and effector systems (inflammasomes, autophagosomes, and ribosomal machinery), controlling cell metabolism and general cell physiology (autophagy and gene expression) [49][50][51][52].…”

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 .…”

“…Functionally, intracellular C3 and C5 can undergo cleavage activation by specific proteases (such as Cathepsin L) or by intracellular C3 and C5 convertases that are generated underneath the plasma membrane and on the surface of subcellular compartments 126,128,147 . Upon the stimulation of intracellular receptors, including C3aR and C5aR1, the complosome can trigger signalling events akin to their cell surface counterparts 16,17 . Nevertheless, it also has the ability to engage with distinct cellular machinery, spatially separated from extracellular complement components, by interacting with new binding partners, underscores its predominantly non‐canonical functions 16 .…”

“…Detailed reviews of this intracellular complement system, termed the "complosome", have been previously published, including recently. [15][16][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][126][127] The complosome is posited to include all complement components with intracellular expression and activity.…”

“…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.…”