Emerging and Novel Functions of Complement Protein C1q

Abstract

Complement protein C1q, the recognition molecule of the classical pathway, performs a diverse range of complement and non-complement functions. It can bind various ligands derived from self, non-self, and altered self and modulate the functions of immune and non-immune cells including dendritic cells and microglia. C1q involvement in the clearance of apoptotic cells and subsequent B cell tolerance is more established now. Recent evidence appears to suggest that C1q plays an important role in pregnancy where its deficiency and dysregulation can have adverse effects, leading to preeclampsia, missed abortion, miscarriage or spontaneous loss, and various infections. C1q is also produced locally in the central nervous system, and has a protective role against pathogens and possible inflammatory functions while interacting with aggregated proteins leading to neurodegenerative diseases. C1q role in synaptic pruning, and thus CNS development, its anti-cancer effects as an immune surveillance molecule, and possibly in aging are currently areas of extensive research.

Keywords: C1q; apoptosis; cancer; complement; neurogenesis; pregnancy.

Figure 1

Structure of C1q. The hexameric C1q molecule (460 kDa) has a tulip-like structure, composed of nine non-covalently linked subunits of six A, B, and C chains; A–B dimer is 52,750 Da and C–C dimer is 47,600 Da. Fragments of C1q after pepsin digestion at pH 4.4 contain six intact connecting strands and small non-collagen-like peptides. After partial proteolysis with collagenase at pH 7.4, the globular regions (gC1q) appear intact. C1q binds to Fc regions of IgG or IgM, HIV-1, phosphatidylserine, HTLV-1, C-reactive protein, damaged neurons, myelin debris, amyloid fibrils, and apoptotic cells via the gC1q domain. The collagen-like region binds to serine proteases such as C1r and C1s leading to activation of the classical pathway. Collagen region of C1q also binds to C1q receptors (most notably, cC1qR or calreticulin using CD91 as a cell-surface adaptor) to augment phagocytosis by phagocytic cells and mount a pro-inflammatory immune response.

Figure 2

Complement activation at the feto-maternal interface during pregnancy. (A) During normal pregnancy, maternal endometrium transforms into feto-maternal interface (decidua) and surrounds the implanted embryo offering nutrition and protection against the maternal immune system. With advancing gestational age, decidua undergoes extensive tissue remodeling (trophoblast invasion and spiral artery formation) that results in apoptotic debris formation. The apoptotic debris and placental IgG activate classical pathway via C1q deposited at the feto-maternal interface. By eliminating the immune complexes and apoptotic cells, complement system protects the mother and fetus. Complement regulatory proteins found on human placental tissues such as Factor H, DAF, MCP, CD46, and CD59 prevent excessive complement activation. (B) In the absence of regulatory proteins (DAF, MCP, CD46, CD59), excessive complement activation results in improper placentation, characterized by increased ROS, inflammatory cytokines, angiogenic proteins (accumulation of apoptotic cells), improper vascularization, and spiral artery remodeling contributing to development of pathological/complicated pregnancies.

Figure 3

Significance of C1q in normal and adverse pregnancy. Absence of C1q results in abnormal invasion of fetal trophoblast into the decidua. C1q deficiency increases oxidative stress and accumulation of apoptotic trophoblasts. This has an adverse effect on placenta inhibiting the generation of placental vascular endothelial growth factor (VEGF) and blood flow, resulting in implantation failure and pregnancy complications such as recurrent pregnancy loss, miscarriage, abortion, and preeclampsia.

Figure 4

Various diseases of central nervous system and the involvement of C1q. various functions of C1q in the central nervous system and the associated diseases are illustrated. Increased levels of C1q have been found in Huntington disease and schizophrenia. In Huntington disease, striatal volume is decreased in mouse models; however, cell number does not differ. Prion disease is a result of undue loss of neurons and misfolded prion protein, PrP^Sc, deposition. Early synaptic failure and neuronal loss affect behavioral symptoms, indicating the early onset of disease. C1q deficiency reduces the capture of prions by DCs, as it is only involved in the primary phase of the disease, transmitting prions to the CNS. C1q production is triggered in the CNS by astrocytes in response to cerebral fungal infection. The role C1q plays in Parkinson’s disease includes the opsonization of neuromelanin and phagocytosis by microglia cells. Complement pathway up-regulation in brain regions can be observed in AD, which may be due to amyloid β peptides binding within collagen-like domain of C1q, thus activating classical pathway. In addition, fibrillar amyloid β interaction with C1q via activates the classical pathway. Microglia cells, which express C1q in the substantia nigra pars compacta of Parkinson disease, phagocytose and clear debris of degenerating neurons.

Figure 5

Serum C1 competes with Wnt for Fz receptor binding, resulting in Wnt canonical pathway activation. Wnt binds to Fz receptor and LRP5/6 which causes β-catenin destruction complex (APC, PP2A, GSK3, and CK1α) by recruiting the Axin component of destruction complex to the cytoplasmic tail of the Wnt co-receptor LRP. This results in stabilization and accumulation of β-catenin in the cytoplasm, which eventually gets translocated into the nucleus to act as a transcriptional co-activator of the TCF/LEF family and the Wnt canonical pathway is activated, which has been shown to induce aging. C1q concentration in the serum increases with age. C1q competes with 200-fold higher binding affinity with Wnt for Fz receptor and stimulates C1s-dependent cleavage of the ectodomain of LRP6. The C1q binding to Fz receptor also blocks the β-catenin destruction complex (APC, PP2A, GSK3, and CK1α) and results in stabilization of β-catenin in the cytoplasm, which is then translocated into the nucleus. Subsequently, canonical Wnt signaling is activated.