Affinage

C1QA

Complement C1q subcomponent subunit A · UniProt P02745

Length
245 aa
Mass
26.0 kDa
Annotated
2026-06-09
33 papers in source corpus 14 papers cited in narrative 14 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 4/5 claims corpus-supported (80%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

C1QA encodes the A-chain of the complement protein C1q, which is produced by myeloid cells: reciprocal bone marrow transfer established that monocyte-macrophage lineage cells, not hepatocytes, are the source of circulating C1q (PMID:11564823), and in the brain microglia are the dominant source, with parenchymal C1q lost upon microglial-specific deletion while peripheral C1q remains intact (PMID:28264694). The protein initiates classical complement activation through electrostatic recognition: a cationic region spanning residues 14–26 of the A-chain mediates charge-dependent binding to anionic surfaces and is required for complement activation on such targets (PMID:10209207). Beyond complement initiation, C1QA participates intracellularly in antiviral signaling, interacting with the RIG-I/VISA pathway to enhance TBK1-driven IFN-β promoter activation and counteracting the inhibitory C1q receptor gC1qR (PMID:22260551), and its expression is constrained post-transcriptionally by METTL3-deposited m6A marks read by YTHDF2 (PMID:37907575). Genetic ablation studies define a host-protective complement role against viral infection (PMID:34056877) and a damaging role in complement-driven neurodegeneration, where microglia-derived C1q mediates retinal ganglion cell and optic nerve loss (PMID:26544197) and is required for activity-dependent elimination of excess proprioceptive Ia afferent connections downstream of proprioceptor activity [PMID:bio_10.1101_2025.08.22.671861]. C1QA also supports basal norrin/FZD4 beta-catenin signaling and blood-retina barrier integrity [PMID:bio_10.1101_2025.07.22.666172], and exerts context-dependent dual effects on injury after intracerebral hemorrhage (PMID:39370487).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1999 High

    Identified the molecular basis by which C1q recognizes activating surfaces, showing that a defined cationic stretch of the A-chain drives complement initiation through electrostatics rather than specific sequence recognition.

    Evidence In vitro binding and inhibition assays with purified C1q, anionic liposomes, and synthetic C1qA14-26 charge-variant peptides plus hemolytic complement assay

    PMID:10209207

    Open questions at the time
    • Does not define the physiological anionic ligands in vivo
    • No structural model of the bound complex
  2. 2001 High

    Resolved the cellular origin of serum C1q, establishing the monocyte-macrophage lineage rather than liver as the source through bidirectional genetic rescue and depletion.

    Evidence Reciprocal bone marrow transplantation in C1qa-/- and wild-type mice with antigenic and hemolytic C1q quantification

    PMID:11564823

    Open questions at the time
    • Does not address tissue-resident vs circulating macrophage contributions
    • Brain source not examined
  3. 2009 Medium

    Showed that a viral protein can subvert C1q-mediated immunity by binding the globular A-chain region, linking C1QA's recognition function to antiviral defense.

    Evidence Co-IP of influenza M1 with C1qA, competition assays against heat-aggregated IgG, hemolysis, neutralization, and murine infection

    PMID:19656971

    Open questions at the time
    • Single lab
    • Physiological relevance of soluble M1 during natural infection unclear
  4. 2012 Medium

    Extended C1QA function beyond extracellular complement to an intracellular role in innate antiviral signaling by potentiating RIG-I/VISA-mediated IFN-β induction.

    Evidence Co-IP of C1qA with RIG-I pathway components and luciferase reporter assays for ISRE, NF-κB, and IFN-β promoters with gC1qR comparison

    PMID:22260551

    Open questions at the time
    • Largely overexpression-based
    • Endogenous intracellular C1qA pool not localized
    • Mechanism of pathway contact unresolved
  5. 2015 Medium

    Established C1q as a causal mediator of complement-driven neurodegeneration by showing C1qa deletion protects retinal ganglion cells and reduces microglial activation in glaucoma.

    Evidence Congenic C1qa KO in DBA/2NNia glaucoma model with RGC/optic nerve scoring, IOP, and microglial morphology

    PMID:26544197

    Open questions at the time
    • Sex-dependent timing unexplained
    • Downstream complement effectors not dissected
  6. 2021 Medium

    Demonstrated that classical complement via C1qa is host-protective against viral infection, complementing the disease-promoting CNS roles.

    Evidence CRISPR/Cas9 C1qa KO mice infected with MHV-A59 with histopathology, viral load, and cytokine quantification

    PMID:34056877

    Open questions at the time
    • Mechanism of protection (opsonization vs lysis) not separated
    • Single coronavirus model
  7. 2023 Medium

    Identified post-transcriptional control of C1QA via m6A, showing METTL3/YTHDF2 suppress C1qA and that restoring it overcomes Rituximab resistance.

    Evidence RIP-qPCR and pulldown identifying METTL3 writer and YTHDF2 reader, with C1QA KD/OE in DLBCL cells, CDC assays, and xenografts

    PMID:37907575

    Open questions at the time
    • Single lab
    • m6A sites on C1QA mRNA not mapped
  8. 2024 Low

    Implicated elevated microglial C1qA in aberrant synaptic pruning in Alzheimer's model brain, correlating it with spine and synaptic protein loss.

    Evidence RNA-seq, immunofluorescence, western blot, Golgi staining, and patch-clamp in FAD4T mice

    PMID:38266812

    Open questions at the time
    • Correlative without direct C1qA manipulation
    • Causality between C1qA and pruning not established in this model
  9. 2024 Low

    Placed C1qA within a tumor-associated macrophage feedback loop promoting M2-like polarization and immune suppression.

    Evidence NLRP12 OE/KD and KO in TAMs with co-culture, NF-κB analysis, and tumor growth assays in lung adenocarcinoma

    PMID:39527158

    Open questions at the time
    • C1qA link inferred from correlation and NLRP12 phenotype
    • Direct C1qA-LILRB4/NF-κB biochemistry not shown
  10. 2024 Medium

    Revealed context-dependent dual roles of C1qa in intracerebral hemorrhage, both promoting erythrolysis/neutrophil infiltration and supporting protective hematoma clearance.

    Evidence C1qa KO mice in autologous blood and thrombin ICH models with MRI and immunohistochemistry

    PMID:39370487

    Open questions at the time
    • Opposing effects across models not mechanistically reconciled
    • Cellular effectors downstream of C1q unclear
  11. 2025 Medium

    Defined a non-canonical C1QA contribution to maintaining basal norrin/FZD4 beta-catenin signaling and blood-retina barrier integrity through genetic epistasis.

    Evidence Compound Tspan12 KO; C1qa KO mice with BRB assays, ERG, edema imaging, and cell-based beta-catenin signaling (preprint)

    PMID:bio_10.1101_2025.07.22.666172

    Open questions at the time
    • Preprint, single lab
    • Direct molecular link between C1qA and FZD4 signaling not established
  12. 2025 Medium

    Positioned C1qA downstream of proprioceptor activity in activity-dependent complement-mediated synapse elimination, showing it is required to prune excess intersegmental Ia afferent connections.

    Evidence Ex vivo spinal cord electrophysiology, C1qa KO and NaV1.6 cKO models, C1qA immunostaining, and Ia afferent tracing (preprint)

    PMID:bio_10.1101_2025.08.22.671861

    Open questions at the time
    • Preprint, single lab
    • Mechanism linking activity to C1qA induction unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How C1QA's distinct extracellular complement-initiating role and its intracellular antiviral and signaling functions are partitioned within and across cell types remains unresolved.
  • No structural basis for intracellular RIG-I pathway contacts
  • Determinants directing C1qA to synaptic vs vascular vs antiviral roles undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005576 extracellular region 2
Pathway
R-HSA-168256 Immune System 3
Complex memberships
C1 complex (C1q)

Evidence

Reading pass · 14 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 Bone marrow-derived cells (monocyte-macrophage lineage) are the source of serum C1q; transplantation of wild-type bone marrow into C1qa-/- mice fully reconstituted serum C1q levels within 6 weeks, while C1qa-/- bone marrow transferred into wild-type mice depleted C1q over 55 weeks. Bone marrow transplantation in C1qa-/- mice; serum C1q quantified by antigen assay and functional hemolytic assay; engraftment monitored by Y-chromosome PCR and genotype-specific PCR Journal of immunology High 11564823
2017 Microglia, not neurons or peripheral sources, are the dominant source of C1q in the brain; conditional knockout of C1qa specifically in microglia (Cx3cr1-Cre) abolished C1q in the brain parenchyma without affecting plasma or peripheral organ C1q levels. Cell-type-specific conditional knockout (C1qa floxed x Cx3cr1-CreERT2); immunohistochemistry, qPCR, and western blot for C1q in brain, liver, kidney, and plasma Journal of neuroinflammation High 28264694
1999 The cationic region comprising residues 14–26 of the C1qA polypeptide chain mediates C1q binding to anionic liposomes via electrostatic interactions; peptides containing this region (with ≥5 cationic residues) inhibited C1q binding to and complement activation by anionic liposomes in a charge-dependent, sequence-independent manner. Saturation binding assay with purified C1q and cardiolipin-containing liposomes; inhibition assays with synthetic C1qA14-26 peptides of varying charge; hemolytic complement activation assay Biochimica et biophysica acta High 10209207
2009 Influenza A virus M1 matrix protein interacts with the globular region of C1qA through M1's N-terminal domain, blocking the interaction between C1qA and heat-aggregated IgG, inhibiting hemolysis, and preventing complement-mediated neutralization of influenza virus in vitro; in vivo, administered M1 promoted higher viral propagation and shortened survival of infected mice. Co-immunoprecipitation of M1 with C1qA; in vitro competition assay (M1 vs. heat-aggregated IgG for C1qA binding); hemolysis assay; neutralization assay; murine in vivo infection model with M1 administration The Journal of general virology Medium 19656971
2012 C1qA interacts with components of the RIG-I/VISA signaling pathway and enhances RIG-I–VISA-mediated and TBK1-mediated activation of the IFN-β promoter; overexpression of C1qA upregulates RIG-I-mediated ISRE and NF-κB reporter activation and IFN-β transcription, but does not affect IRF3- or IKK-mediated ISRE/NF-κB activation; C1qA also counteracts the inhibitory function of the C1q receptor gC1qR in RIG-I-mediated signaling. Co-immunoprecipitation of C1qA with RIG-I pathway components; luciferase reporter assays for ISRE, NF-κB, and IFN-β promoters upon C1qA overexpression; functional comparison with gC1qR Immunology Medium 22260551
2023 C1qA expression is regulated at the post-transcriptional level by METTL3-mediated m6A methylation; YTHDF2 acts as the m6A reader for C1qA mRNA; knockdown of METTL3 or YTHDF2 in Rituximab-resistant DLBCL cells upregulates C1qA expression, and restoring C1qA expression reduces Rituximab resistance both in vitro and in vivo. RNA immunoprecipitation with qPCR (RIP-qPCR); pulldown assays to identify METTL3 (writer) and YTHDF2 (reader); C1qA knockdown and overexpression in sensitive and resistant cell lines; in vitro CDC assays; xenograft mouse model Cell death discovery Medium 37907575
2015 C1qa deletion in DBA/2NNia mice reduces retinal ganglion cell and optic nerve axonal loss in a sex-dependent manner (protective in males at 9–10 months, protective in females at 11–13 months), and decreases microglial activation in male mice at 5–6 months, establishing C1q as a mediator of complement-driven RGC damage in glaucoma. Congenic C1qa knockout mice in glaucoma model; retrograde labeling and semi-quantitative scoring of RGC and optic nerve; IOP measurement; microglial morphology assessment in flat-mounted retinas PloS one Medium 26544197
2021 C1qa deficiency (CRISPR/Cas9 KO) enhances susceptibility to mouse hepatitis virus A59, resulting in more severe hepatocellular necrosis and interstitial pneumonia, higher viral loads in olfactory bulb, liver, and lungs, and dramatic elevations in splenic IFN-γ, MIP-1α, and MCP-1, demonstrating that classical complement pathway activation via C1qa is required for host protection against coronavirus infection. CRISPR/Cas9-generated C1qa KO mice; MHV-A59 infection model; histopathology; immunohistochemistry; quantitative viral load measurement; chemokine/cytokine quantification Journal of veterinary science Medium 34056877
2024 In an AD mouse model (FAD4T), elevated C1qA protein and mRNA in activated microglia is associated with aberrant synaptic pruning leading to reduced dendritic spine density, decreased PSD-95 and NMDAR1 levels, and impaired miniature excitatory postsynaptic current amplitudes. RNA-seq; immunofluorescence; western blot; Golgi staining for dendritic spines; patch-clamp electrophysiology in hippocampal neurons Life sciences Low 38266812
2024 C1qa knockout mice exhibit reduced hematoma erythrolysis, reduced neutrophil infiltration after intracerebral hemorrhage, but also delayed hematoma clearance associated with reduced induction of phagocytic multinuclear giant cells and increased perihematomal neuronal damage; after thrombin injection, C1qa KO mice had smaller lesion volumes, less neuronal loss, reduced neutrophil infiltration, and less BBB damage, indicating dual and context-dependent roles of C1qa in ICH-induced brain injury. C1qa KO mice; autologous blood injection and thrombin injection ICH models; MRI on days 1, 3, 7; immunohistochemistry for neutrophils, neurons, BBB markers, and phagocytic cells Translational stroke research Medium 39370487
2024 NLRP12 forms a positive feedback loop with C1qA in tumor-associated macrophages (TAMs) to drive protumor M2-like polarization via the LILRB4/NF-κB pathway; NLRP12 knockout reversed macrophage polarization, enhanced T-cell anti-tumor immunity, and suppressed tumor growth in lung adenocarcinoma models. NLRP12 overexpression and knockdown in TAMs; NLRP12 KO mouse model; co-culture with tumor cells and T cells; NF-κB pathway analysis; tumor growth assays Cancer immunology, immunotherapy Low 39527158
2032 Silencing C1QA in high-glucose-treated human renal tubular epithelial cells (HK-2) attenuated suppression of proliferation and reduced apoptosis, and concurrently downregulated endoplasmic reticulum stress effector proteins CHOP, XBP1s, and ATF6, indicating C1QA promotes HG-induced tubular epithelial injury by potentiating ERS. C1QA siRNA knockdown in HK-2 cells under high glucose conditions; CCK-8 viability assay; EdU proliferation assay; flow cytometry for apoptosis; western blot for ERS markers (CHOP, XBP1s, ATF6) Gene Medium 42242331
2025 C1QA contributes to maintaining basal beta-catenin-dependent (norrin/FZD4) signaling in the retina; absence of C1QA in compound Tspan12 KO DBM; C1qa KO mice exacerbates blood-retina barrier dysfunction, cystoid edema, and neuroinflammation compared to Tspan12 KO DBM alone. Compound mutant mice (Tspan12 KO DBM; C1qa KO); BRB functional assays; MRI/imaging for cystoid edema assessment; ERG; microglia activation analysis; cell-based beta-catenin signaling assays bioRxivpreprint Medium bio_10.1101_2025.07.22.666172
2025 C1qA-deficient (C1qa KO) neonatal mice retain intersegmental proprioceptive Ia afferent connections at P11–13 that are normally eliminated by P11–13, phenocopying NaV1.6 conditional KO mice with impaired proprioceptor activity; NaV1.6 cKO mice show reduced C1qA expression in ventral spinal cord at P9, placing C1qA downstream of proprioceptor activity in complement-mediated elimination of excessive intersegmental synaptic connectivity. Ex vivo spinal cord electrophysiology in neonatal mice; C1qa KO and NaV1.6 cKO genetic models; immunostaining for C1qA expression; anatomical tracing of proprioceptive Ia afferents bioRxivpreprint Medium bio_10.1101_2025.08.22.671861

Source papers

Stage 0 corpus · 33 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2017 Cell-specific deletion of C1qa identifies microglia as the dominant source of C1q in mouse brain. Journal of neuroinflammation 292 28264694
2008 A polymorphism in the complement component C1qA correlates with prolonged response following rituximab therapy of follicular lymphoma. Clinical cancer research : an official journal of the American Association for Cancer Research 119 18927313
2001 Reconstitution of the complement function in C1q-deficient (C1qa-/-) mice with wild-type bone marrow cells. Journal of immunology (Baltimore, Md. : 1950) 96 11564823
2020 Increased Macrophages and C1qA, C3, C4 Transcripts in the Midbrain of People With Schizophrenia. Frontiers in immunology 78 33133060
2003 Homozygous single nucleotide polymorphism of the complement C1QA gene is associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus. Lupus 66 12630757
1999 C1q binding to liposomes is surface charge dependent and is inhibited by peptides consisting of residues 14-26 of the human C1qA chain in a sequence independent manner. Biochimica et biophysica acta 56 10209207
2009 Influenza A virus M1 blocks the classical complement pathway through interacting with C1qA. The Journal of general virology 42 19656971
2024 Cognitive impairment in Alzheimer's disease FAD4T mouse model: Synaptic loss facilitated by activated microglia via C1qA. Life sciences 29 38266812
2006 The pattern of clinical breast cancer metastasis correlates with a single nucleotide polymorphism in the C1qA component of complement. Immunogenetics 26 16465510
2012 The complement C1qA enhances retinoic acid-inducible gene-I-mediated immune signalling. Immunology 25 22260551
2010 Common germ-line polymorphism of C1QA and breast cancer survival. British journal of cancer 16 20332777
2019 C1QA and C1QC modify age-at-onset in familial amyloid polyneuropathy patients. Annals of clinical and translational neurology 15 31019999
2010 Hereditary C1q deficiency: a new family with C1qA deficiency. The Turkish journal of pediatrics 15 20560256
2012 Association study of C1qA polymorphisms with systemic lupus erythematosus in a Han population. Lupus 14 22236909
2012 Identification of novel coding mutation in C1qA gene in an African-American pedigree with lupus and C1q deficiency. Lupus 13 22472776
2015 Differential Effects of C1qa Ablation on Glaucomatous Damage in Two Sexes in DBA/2NNia Mice. PloS one 12 26544197
2020 A regulatory variant in the C1Q gene cluster is associated with tuberculosis susceptibility and C1qA plasma levels in a South African population. Immunogenetics 11 32556499
2024 C1QA is an invariant biomarker for tissue macrophages. bioRxiv : the preprint server for biology 10 38328228
2023 METTL3-mediated m6A methylation of C1qA regulates the Rituximab resistance of diffuse large B-cell lymphoma cells. Cell death discovery 10 37907575
2022 Potential biomarkers of spinal dural arteriovenous fistula: C4BPA and C1QA. Journal of neuroinflammation 10 35733178
2023 C1QA and COMP: plasma-based biomarkers for early diagnosis of pancreatic neuroendocrine tumors. Scientific reports 9 38030709
2022 In silico analysis of missense variants of the C1qA gene related to infection and autoimmune diseases. Journal of Taibah University Medical Sciences 9 36212588
2022 Multi-omics profiling identifies C1QA/B+ macrophages with multiple immune checkpoints associated with esophageal squamous cell carcinoma (ESCC) liver metastasis. Annals of translational medicine 8 36544679
2024 NLRP12/C1qA positive feedback in tumor-associated macrophages regulates immunosuppression through LILRB4/NF-κB pathway in lung adenocarcinoma. Cancer immunology, immunotherapy : CII 6 39527158
2021 C1qa deficiency in mice increases susceptibility to mouse hepatitis virus A59 infection. Journal of veterinary science 5 34056877
2024 Identification of the C1qDC gene family in grass carp (Ctenopharyngodon idellus) and the response of C1qA, C1qB, and C1qC to GCRV infection in vivo and in vitro. Fish & shellfish immunology 3 38447782
2024 The Role of Complement C1qa in Experimental Intracerebral Hemorrhage. Translational stroke research 3 39370487
2026 Mechanotransduction unifies healthy nondiabetic wound healing over time by promoting a Cd14+/C1qa+ fibroblast subpopulation. The Journal of investigative dermatology 1 41997300
2025 Monogenic lupus with neuroregression in an infant due to rare compound heterozygous variants in C1QA gene: Case-based review. Modern rheumatology case reports 1 39096524
2024 Correlation between Complement C1q A Chain (C1QA) and Macrophages in the Progression of Carotid Atherosclerosis. Iranian journal of public health 1 39086409
2026 Homozygous C1qA Deficiency Presenting as Early-Onset Systemic Lupus Erythematosus: A Case Report With a Literature Review. Case reports in immunology 0 42147803
2026 Single-cell-based analysis establishes C1QA-mediated promotion of high glucose-induced tubular epithelial injury via ERS in DN. Gene 0 42242331
2025 Investigation of miR-335-5p and Its Target Gene C1QA Associated with the Complement System in Conversion from Clinically Isolated Syndrome to Multiple Sclerosis. Noro psikiyatri arsivi 0 41383891

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