Human C5 Protein

The complement system is an important component of the innate immune system, including more than 50 membrane-bound and soluble proteins, which can play an important role in defense against pathogens as well as in maintaining the dynamic balance of the body. Complement can be activated by three pathways, including the classical pathway, the lectin pathway, and the bypass pathway, all of which share a common terminal pathway. The complement activation pathway can be divided into four major steps, namely complement activation, C3 convertase formation, C5 convertase generation, and membrane attack complex (MAC) assembly. The MAC creates pores in the cell membrane that lead to the destruction of target cells.

The main source of C5 in plasma is hepatocytes, whereas other cell types are also involved in the local synthesis of C5, such as neutrophils, fibroblasts, and monocytes/macrophages. The protein was initially synthesized as a precursor form containing 1676 amino acids and was processed by proteolytic hydrolysis by protease removal of the N-terminal signal peptide and an internal 4-residue fragment prior to secretion. When analyzed by reduced SDS-PAGE under reducing conditions, the protein showed two chains, including a 115kD α chain and a 75kD β chain. C5 is broken down into C5a and C5b by C5 converting enzyme. C5b triggers complement components C6-C9 thereby assembling the MAC. C5a is one of the most critical activation products of the human complement system, which acts through the receptors C5aR1 and C5aR2. C5a binding and activation of C5aR elicits a variety of immune effects in vivo, such as chemotaxis and activation of cells and activation of inflammatory signals. C5a and C3a can promote phagocytosis by recruiting cells expressing receptors for C3 and C4 fragments.

Figure 1. Activation of C5 by C5 convertase leads to the generation of C5a and C5b
(Source: Horiuchi T, et al. 2016)

The intracellular complement system is a relatively independent intracellular immune system that can regulate the function of the corresponding cells, and C5 complement proteins are also present in a wide range of cells, but it is not clear exactly where C5 is localised within the cell. Activation of intracellular C5 in CD4⁺ T cells is involved in the formation of Th1 cells. Under the combined action of TCR and CD46, intracellular C5 is cleaved into C5a and C5b, and the generated C5a binds to C5aR1, which is expressed only intracellularly, to induce ROS generation. ROS production promotes the assembly of NLRP3 inflammatory vesicles and the secretion of IL-1β which in turn maintains the Th1 response.

Human complement C5
Human complement component 5