The complement system is part of the body's innate immune system, and it plays a role in resisting the invasion of foreign microorganisms and clearing immune complexes and damaged cells. Due to its strong potential to produce inflammation and cause tissue destruction, under normal circumstances, complement is strictly controlled by many liquid and cell surface proteins to avoid damaging autologous tissue.
Activation of the classical complement pathway (CP) and the lectin pathway (LP) depends to a large extent on foreign substances, but in some cases (such as tissue ischemia and reperfusion), both pathways can be activated and causes auto-injury. More relevant to complement-related human diseases, activation and expansion of C3b deposition through alternative pathways (AP) is non-discriminatory and, if not properly regulated, may rapidly damage host cells. Therefore, it is essential that the activity on the host cell is down-regulated while allowing efficient activation on the foreign target. Humans and other mammals have developed a variety of plasma and membrane-binding inhibitory proteins to regulate complement location and activity. These molecules regulate complement activation in different steps of the complement cascade, participate in the removal of complement-coated particles and / or protect host cells from damage.
Fig. 1 Schematic diagram of complement regulation.1
Complement Regulator of Complement System: C1 Inhibitor / C1INH / SERPING1
C1 inhibitors (C1INH) irreversibly bind and inactivate C1r and C1s of CP and MASP-1 and MASP-2 of LP, thereby inhibiting the initial steps of these activation pathways. C1INH deficiency causes paroxysmal angioedema. In addition to its role as a complement inhibitor, C1INH is also a major inhibitor of factor XIIa and kallikrein in the system. C1INH's insufficient inhibition of these enzymes can lead to inappropriate bradykinin production. This in turn mediates the vascular permeability characteristic of angioedema.
Complement Regulator of Complement System: Protectin / CD59
CD59 is a key regulator of the terminal pathway. It inhibits the association of C9 with C5b-8 to prevent the formation of C5b-9. Both CD59 and DAF are immobilized on the cell membrane by glycosylphosphatidylinositol molecules. Somatic mutations of the phosphatidylinositol-complementing class A gene in red blood cells can cause a rare clonal disease called paroxysmal nocturnal hemoglobinuria. Patients suffer from a deficiency in phosphatidylinositol-complex class A function, causing affected red blood cells lack all glycosylphosphatidylinositol-linked membrane proteins associated with autocomplement-mediated hemolytic anemia.
Complement Regulator of Complement System: Vitronectin / VTN
Vitronectin, also known as protein S, is one of the Terminal Membrane Attack Complex (MAC) modulators. It preferentially binds C5b-7 and interacts with C9 to form SC5b-9, thereby inhibiting its polymerization reaction. In addition, vitronectin is a component of platelets and therefore participates in hemostasis. Vitronectin contains an RGD (45-47) sequence, which is a binding site for membrane-bound integrins, such as the vitronectin receptor, which is used to anchor cells to the extracellular matrix.
Complement Regulator of Complement System: Clusterin / CLU
Clusterin (CLU) is another complement modulator that not only acts as a component of C5b-7 at the level of C7, prevents the complex from inserting into the cell membrane, but also binds to C8 and C9, thereby inhibiting the polymerization of C9. CLU is a member of the small heat shock protein family and is therefore a molecular chaperone. Unlike most other chaperone proteins that help intracellular proteins, CLU is a Golgi protein chaperone that promotes the folding of secreted proteins in an ATP-independent manner. In addition to protecting its own cells in the complement pathway, CLU can promote cell survival in a variety of ways, including inhibiting BAX on the mitochondrial membrane, activating the phosphatidylinositol 3-kinase / protein kinase B pathway, and regulating extracellular signal-regulated kinase ( ERK) 1/2 signaling and matrix metallopeptidase-9 expression promote angiogenesis and mediate the nuclear factor-κB (NF-κB) pathway.
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Reference
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Morgan, B. Paul, and Claire L. Harris. "Complement, a target for therapy in inflammatory and degenerative diseases." Nature reviews Drug discovery 14.12 (2015): 857-877.
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