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Review
. 2017 May 24;8:592.
doi: 10.3389/fimmu.2017.00592. eCollection 2017.

C1 Complex: An Adaptable Proteolytic Module for Complement and Non-Complement Functions

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Free PMC article
Review

C1 Complex: An Adaptable Proteolytic Module for Complement and Non-Complement Functions

Jinhua Lu et al. Front Immunol. .
Free PMC article

Abstract

Complement C1 is the defining component of the classical pathway. Within the C1qC1r2C1s2 complex, C1q functions as a molecular scaffold for C1r2C1s2 and C1q binding to its ligands activates these two serine proteases. The classic C1q ligands are antigen-bound antibodies and activated C1s cleaves C4 and C2 to initiate the complement cascade. Recent studies suggest broad C1 functions beyond the complement system. C1q binds to the Frizzled receptors to activate C1s, which cleaves lipoprotein receptor-related protein 6 to trigger aging-associated Wnt receptor signaling. C1q binds to apoptotic cells and the activated C1 proteases cleave nuclear antigens. C1s also cleaves MHC class I molecule and potentially numerous other proteins. The diversity of C1q ligands and C1 protease substrates renders C1 complex versatile and modular so that it can adapt to multiple molecular and cellular processes besides the complement system.

Keywords: C1q; aging; autoimmunity; complement C1; dendritic cell; infection; inflammation; macrophage.

Figures

Figure 1
Figure 1
The complement protein and protease network. The complement system operates via three target recognition pathways: the classical, alternative, and lectin pathways. All pathways recognize microorganisms and apoptotic cells and the recognition subcomponents are in green. Upon its triggering via any of the three pathways, the complement acts through three effector reactions: the C8-C9 lytic or membrane attack complex, the soluble C3a and C5a anaphylatoxins (blue color), and surface-bound C3b, C4b, and further proteolytic fragment opsonins (orange color with green asterisk). All three pathways converge at the C3 component and complement reactions are essentially amplified through cascades of serine proteases (red color). MBL, mannose-binding lectin; MASPs, MBL-associated serine proteases; fB, factor B; fD, factor D; fI, factor I; fH, factor H. Homozygous deficiency of C1q, C1r/C1s, or C4 is causally associated with systemic lupus erythematosus (SLE) pathogenesis. Genetic C2 deficiency also increases risk for SLE and some other autoimmune diseases.
Figure 2
Figure 2
Schematic illustration of the cellular origin of C1q, its assembly, and three distinct modular functions of C1 complex. C1q is an abundant plasma protein. It can be produced broadly in tissues by macrophages and DCs, which also produce C1r/C1s. C1q is formed from three similar but distinct subunits, i.e., A, B, and C, and the order of assembly is illustrated. Inter-subunit disulfide bonds (purple bars) and the collagen-like helices defines the sorting of the three subunits within the C1q polypeptide. In the serum, C1q is associated with the serine protease proenzyme tetramer C1r2C1s2 to form the C1 complex. In this complex, C1q binds to diverse targets that activate the serine proteases and the proteases trigger effector reactions by cleaving specific substrate. Three physiological contexts are highlighted in which the C1 complex is known to play a role. When C1q binds to antibodies on microbial pathogens, the activated C1s cleaves complement C4 and C2 to initiate the proteolytic cascade. When C1q binds to Frizzled, activated C1s cleaves lipoprotein receptor-related protein 6 to cause canonical Wnt signaling and accelerated aging. When C1q binds to apoptotic cells, the activated C1s cleaves apoptotic cellular antigens to reduce autoimmunogenicity. The red arrows indicate C1s cleavage of the specific substrate.
Figure 3
Figure 3
Schematic illustration of C1q gene organization, gene transcription, and multimeric C1q assembly. (A) The three human C1q genes span approximately 25 kb on human chromosome 1. The intergenic regions are 4.0 and 5.1 kb, respectively, which are not distinguishable in size from regular introns in the C1q genes. Each of the three C1q genes contains three exons and the transcribed peptides form disulfide-linked A-B hererodimers and C-C homodimers. Each C chain in the homodimer forms a collagen triple-helix with an A-B heterodimer, and hence, two triple-helices linked by the disulfide bond in the C-C dimer. Three such ABC-CBA twin helices associate non-covalently over the N-terminal ends to form the 18-polypeptide C1q molecule. The gC1q domains are often the ligand-binding sites for C1q and the collagen triple-helices associate with the C1r2C1s2 serine protease tetramer. (B) Conservation of the C1q gene organization in eight different animal species. The three C1q genes in chimpanzee occupied the largest genomic space which is approx. 27 kb. In chickens, the three C1q genes occupied merely 7.7 kb with intergenic sequences of 0.7 and 1.3 kb, respectively.
Figure 4
Figure 4
Schematic proposal how C1 deficiency may cause systemic lupus erythematosus pathogenesis. In live cells, the nucleus and other intracellular structures are compartmentalized and excluded from complement recognition. When cells undergo apoptosis, the nucleus and other cellular structures disintegrate and, in late apoptotic cells, these fragments are recognized by C1q, which opsonize apoptotic cells for phagocytosis. This can also cause C1r/C1s activation and the activated C1s could cleave its classic substrate C4 and C2 and produce complement opsonins for phagocytosis. C1s may also cleave numerous exposed nuclear and other cellular proteins that are otherwise autoimmunogenic (autoantigens) and cause B cell production of autoantibodies. C1s may also cleave cellular proteins that are otherwise pro-inflammatory danger-associated molecular patterns (DAMPs) and activate DCs to cause B cell production of pathogenic IgG autoantibodies. C1s may not inactivate all autoantigens but effective inactivation of DAMPs can abrogate class switch of autoantibodies from IgM to pathogenic IgG.

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