Complement component C3 – The “Swiss Army Knife” of innate immunity and host defense

Abstract

Summary As a preformed defense system, complement faces a delicate challenge in providing an immediate, forceful response to pathogens even at first encounter, while sparing host cells in the process. For this purpose, it engages a tightly regulated network of plasma proteins, cell surface receptors, and regulators. Complement component C3 plays a particularly versatile role in this process by keeping the cascade alert, acting as a point of convergence of activation pathways, fueling the amplification of the complement response, exerting direct effector functions, and helping to coordinate downstream immune responses. In recent years, it has become evident that nature engages the power of C3 not only to clear pathogens but also for a variety of homeostatic processes ranging from tissue regeneration and synapse pruning to clearing debris and controlling tumor cell progression. At the same time, its central position in immune surveillance makes C3 a target for microbial immune evasion and, if improperly engaged, a trigger point for various clinical conditions. In our review, we look at the versatile roles and evolutionary journey of C3, discuss new insights into the molecular basis for C3 function, provide examples of disease involvement, and summarize the emerging potential of C3 as a therapeutic target.

Regulator-dependent mechanisms of C3b processing by factor I allow differentiation of immune responses

“…Degradation of C3b by cofactor-assisted FI cleavage is critical for protection of host cells from complement attack and for processing of opsonized microbes and apoptotic host cells to invoke cellular responses 45 . The presented crystal structures reveal how the human regulator FH assists in binding FI to the C3b–FH complex and how the complex activates FI to cleave C3b at its first cleavage site.…”

Novel mechanisms and functions of complement

“…Other studies provided molecular insight into the assembly, function and regulation of the alternative pathway C3 convertase (C3bBb) 5 . An intricate mechanism driven by conformational changes and tiered interactions enables instant opsonic reactivity while restricting the response to immediate sites of activation 118 (Fig.…”

“…Advances in biophysical methods, especially cryogenic electron microscopy 4 , have led to an increasingly refined picture not only of individual complement components but also of intricate complexes, such as the C3 convertases or the MAC 5,6 . We thus begin to understand their dynamic conversions and interactions, are able to map and predict the molecular and functional consequences of genetic alterations in complement proteins, and design and rationalize therapeutic strategies.…”

Production of complement components by cells of the immune system

“…CR1 (CD35) is both a complement receptor for C3b, iC3b and C4b and a complement inhibitor, by competing with factor B (FB) for C3b binding and by functioning as a co-factor for factor I (FI) [6]. CR2 (CD21) binds iC3b, and especially C3d/C3dg, CR3 (MAC-1, CD11b/CD18) binds iC3b and C3d/C3dg, whereas CR4 (gp150/95, CD11c/CD18) binds only iC3b [7][8][9][10][11][12]. Another complement receptor, complement receptor of the immunoglobulin superfamily (CRIg), binds to C3b and iC3b and also to soluble C3c [13,14].…”