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

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.

Broad Susceptibility of Nucleolar Proteins and Autoantigens to Complement C1 Protease Degradation

“…Our results resonate with an earlier prediction that, besides its complement substrates, C1s potentially cleaves many intracellular proteins (55). In fact, C1s is also known to cleave cell surface receptors and the secreted insulin-like growth factor binding protein 5 (56).…”

Deiminated proteins in extracellular vesicles and serum of llama (Lama glama)—Novel insights into camelid immunity

“…Complement also has roles in regeneration (Del Rio-Tsonis et al, 1998;Haynes et al, 2013) and tissue remodelling (Lange et al, 2004a(Lange et al, , 2004bLange et al, 2005Lange et al, , 2006Lange et al, , 2019. Furthermore, C1 is also implicated in multiple non-complement functions including binding of apoptotic cells, cleavage of nuclear antigens and cleavage of MHC class I (Lu and Kishore, 2017). Post-translational deimination of complement components may possibly influence their function including cleavage ability, binding, deposition and generation of the convertase.…”

The Complement System and C1q in Chronic Hepatitis C Virus Infection and Mixed Cryoglobulinemia

“…The liver makes ~90% of the plasma components of classical, alternative, and lectin pathways. By contrast, whereas hepatocytes are the predominant source of C1r and C1s in blood, activated monocytes/macrophages and immature dendritic cells are the primary source of C1q, a recognition molecule for classical pathway activation that also has significant non-complement functions ( 19 ). Although the liver produces the majority of C4, multiple tissues may also produce this protein for local consumption, particularly in response to interferon-gamma ( 20 ).…”

“…Based on evidence that C1q and HCV-core bind to gC1qR, gC1qR/HCV-core complexes might provide a platform for complement activation and deposition of C4D at sites of vasculopathy ( 83 ). Additional factors that might be reflected in depletion of C4/C1q and localization to cryocomplexes include the ability of C1q to bind promiscuously to >100 known ligands, including both IgG- and IgM-containing immune complexes, surface-bound C-reactive protein, and molecules exposed at the surface of apoptotic cells, with binding through charged residues on the apex of the gC1q heterotrimer ( 19 , 84 ), acquired C1-inhibitor deficiency ( 85 ), regulation of activation by C4-binding protein ( 86 , 87 ), and antibodies to C1q and/or potentially to other components of the C1 complex ( 88 ).…”