{"gene":"C1QC","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":2003,"finding":"Crystal structure of the C1q globular domain resolved to 1.9 Å reveals a compact heterotrimeric assembly (comprising the C-terminal globular regions of the A, B, and C chains, including C1QC) held together mainly by non-polar interactions with a Ca2+ ion bound at the top; structural models suggest this heterotrimeric arrangement underlies C1q's versatile ligand-recognition properties and indicates plausible binding modes for CRP and IgG.","method":"X-ray crystallography at 1.9 Å resolution","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional modeling, foundational paper with >280 citations","pmids":["12960167"],"is_preprint":false},{"year":1991,"finding":"The genes encoding the A, B, and C chains of human C1q (including C1QC) are arranged in tandem (5'→3' order A-C-B) on a 24 kb stretch of chromosome 1p; the C-chain gene is ~3.2 kb with one intron located within a codon for a glycine residue in the collagen-like region; the complete derived amino acid sequence of C1QC was determined, completing the full C1q sequence.","method":"cDNA cloning, cosmid library isolation, DNA sequencing, Southern blot","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — direct sequencing and genomic characterization, foundational paper with >190 citations","pmids":["1706597"],"is_preprint":false},{"year":1979,"finding":"The complete amino acid sequence of the collagen-like region of the C1q C-chain (C1QC) was determined, revealing that continuity of the Gly-X-Y repeating triplet is broken at position C-36 where alanine replaces glycine, a feature shared with the B-chain, suggesting a structural basis for the bending observed in electron microscopy of C1q.","method":"Amino acid sequencing","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 — direct protein sequencing, foundational paper with >110 citations","pmids":["486087"],"is_preprint":false},{"year":2006,"finding":"Mutational analysis of recombinant globular head modules of the C1q C chain (ghC) demonstrated that charged residues at the apex of the heterotrimeric gC1q domain (involving all three chains, including ghC) are critical for binding to IgG1, CRP, and PTX3; contribution of each chain differs per ligand, suggesting a shared ionic/hydrogen-bond interaction surface rather than separate discrete binding sites.","method":"Recombinant globular head module expression, site-directed mutagenesis, binding assays (ELISA/SPR)","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis combined with functional binding assays, >120 citations","pmids":["16566583"],"is_preprint":false},{"year":2003,"finding":"Experiments with recombinant globular head domains of C1q A, B, and C chains showed that the C1q globular head region (including the C-chain/C1QC) mediates binding to pentraxin 3 (PTX3); PTX3 bound to immobilized C1q activates the classical complement pathway (C4 deposition), whereas fluid-phase PTX3-C1q complexes inhibit complement activation by blocking C1q-immunoglobulin interaction.","method":"Recombinant globular head domain binding assays, C4 deposition assay, dose-response experiments","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 — reconstitution and functional complement assays, >280 citations","pmids":["12645945"],"is_preprint":false},{"year":2008,"finding":"C1q binds phosphatidylserine (PS) on apoptotic cells through its globular domain (the heterotrimer including C1QC); X-ray crystallography confirmed direct C1q globular domain–PS interaction, with KD = 3.7–7×10⁻⁸ M via interactions with the phosphoserine group; confocal microscopy showed C1q colocalizes with PS in membrane patches at early stages of apoptosis.","method":"Surface plasmon resonance, cosedimentation, X-ray crystallography, confocal microscopy, annexin V competition assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 — multiple orthogonal methods including crystallography and SPR, >220 citations","pmids":["18250442"],"is_preprint":false},{"year":2014,"finding":"IgG hexamers formed via noncovalent Fc-Fc interactions after antigen binding recruit and activate the C1 complex (containing C1QC as part of the C1q heterotrimer); manipulation of Fc-Fc interactions modulated complement activation and target cell killing across all four IgG subclasses, providing a model for antibody-mediated complement activation.","method":"Cryo-EM, native mass spectrometry, cell-killing assays, engineered IgG mutants","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — structural and functional reconstitution with mutagenesis, >630 citations","pmids":["24626930"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structures of C1 bound to IgG1 hexamers revealed distinct C1q binding sites on both Fc-CH2 domains of each IgG molecule; upon antibody binding, C1q arms condense, inducing rearrangement of C1r2s2 proteases and tilting C1q's cone-shaped stalk, suggesting C1r activation of C1s can occur within single strained C1 complexes or between neighboring complexes on surfaces.","method":"Cryo-electron microscopy, IgG1 mutant functional analysis","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM with mutant validation, >140 citations","pmids":["29449492"],"is_preprint":false},{"year":1991,"finding":"HIV-1 gp41 directly binds C1q (but not C1s dimers), and synthetic peptides spanning positions 591–605 and 601–620 of gp160 mediate both C1q binding and C1 complex activation leading to C3 deposition; this identifies specific sites in gp41 that engage C1 (containing C1QC) independent of antibody.","method":"Gel exclusion chromatography, radiolabeled C1q binding, recombinant protein binding assay, synthetic peptide competition","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 1-2 — reconstituted binding and activation assays with peptide mapping, >185 citations","pmids":["1744579"],"is_preprint":false},{"year":2009,"finding":"C1q (the heterotrimer including C1QC) binds to plasmacytoid dendritic cells (PDCs) as demonstrated by surface plasmon resonance and flow cytometry, and inhibits immune complex- and CpG-induced IFN-α production by PDCs; this regulatory function links C1q deficiency to the type I IFN upregulation characteristic of SLE pathogenesis.","method":"Surface plasmon resonance, flow cytometry, cytokine immunoassay, PBMC/PDC stimulation assays","journal":"Arthritis and rheumatism","confidence":"High","confidence_rationale":"Tier 2 — reciprocal binding plus functional cytokine readout, >145 citations","pmids":["19790049"],"is_preprint":false},{"year":2019,"finding":"A compound heterozygous mutation in C1QC (c.100G>A p.Gly34Arg and c.205C>T p.Arg69X on different chromosomes confirmed by RNA sequencing) results in complete absence of C1q protein in serum, causing classical-pathway complement deficiency and associated SLE with cerebral involvement.","method":"ELISA, Western blot, DNA sequencing, RNA sequencing","journal":"Lupus","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function genotype confirmed by protein-level assays in a clinical case","pmids":["31357913"],"is_preprint":false},{"year":2024,"finding":"Under diabetic conditions, C1QC is upregulated in cerebral microvascular endothelial cells; C1QC binds to discoidin domain receptor 2 (DDR2) and activates downstream MMP9, a calcium-dependent matrix metalloprotease that degrades extracellular matrix components, leading to structural and functional disruption of the blood-brain barrier; siRNA-mediated C1QC suppression mitigated BBB damage in vitro and in vivo.","method":"Bioinformatics, in vivo diabetic mouse model, in vitro high-glucose cell model, siRNA knockdown, Western blot, co-immunoprecipitation/binding assay","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD with defined molecular pathway (C1QC→DDR2→MMP9→BBB disruption), single lab","pmids":["39531193"],"is_preprint":false},{"year":2025,"finding":"In diabetic kidney disease, C1QC is upregulated in proximal tubular cells under high glucose/palmitate stress; C1QC knockdown attenuates lipid accumulation and inflammation whereas C1QC overexpression exacerbates them; the SGLT2 inhibitor empagliflozin confers renoprotection partly by downregulating C1QC, and C1QC overexpression partially reverses empagliflozin's protective effects in vitro and in db/db mice.","method":"siRNA knockdown, plasmid overexpression, empagliflozin pharmacological intervention, in vivo db/db mouse model, rescue experiments","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — gain/loss-of-function with rescue in both in vitro and in vivo models, single lab","pmids":["41252098"],"is_preprint":false},{"year":2025,"finding":"In ischemic stroke (MCAO/R model), circDnajc1 acts as a sponge for miR-27a-5p, relieving miR-27a-5p-mediated suppression of C1qc; elevated C1qc promotes microglial activation, upregulates C3 and C5aR, drives inflammatory factor release and neuronal apoptosis; circDnajc1 knockdown inhibits microglial activation and is neuroprotective through this axis; validated by RNA immunoprecipitation and luciferase reporter assays.","method":"MCAO/R rat model, OGD/R cell model, siRNA/overexpression, RT-qPCR, immunofluorescence, flow cytometry, RNA immunoprecipitation, luciferase reporter assay","journal":"Molecular neurobiology","confidence":"Medium","confidence_rationale":"Tier 2-3 — pathway placement via RIP and luciferase assays with in vivo validation, single lab","pmids":["40483386"],"is_preprint":false},{"year":2024,"finding":"In grass carp, recombinant C1qC protein (rC1qC) exerts a substantial inhibitory effect on grass carp reovirus (GCRV) replication in CIK cells after 24 h of GCRV inoculation, demonstrating direct antiviral activity for the C1qC protein in a teleost model.","method":"Recombinant protein incubation assay, viral replication quantification in cell culture","journal":"Fish & shellfish immunology","confidence":"Low","confidence_rationale":"Tier 3 — single method in non-mammalian organism (fish ortholog), single lab","pmids":["38447782"],"is_preprint":false},{"year":2011,"finding":"FAP+ fibroblasts secrete WNT2 to activate β-catenin signaling in macrophages, upregulating C1QC and M2 markers; C1QC+ macrophages then exhibit enhanced fatty acid metabolism, secrete CCL2 to recruit Tregs, and induce T cell exhaustion; inhibition of FAP reshaped the immune landscape by reducing C1QC+ macrophage infiltration.","method":"scRNA-seq, spatial transcriptomics, co-culture systems, in vivo OSCC mouse model, FAP inhibition, multi-omics","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2-3 — WNT2→β-catenin→C1QC axis defined by co-culture and in vivo experiments, single lab","pmids":["41831519"],"is_preprint":false},{"year":2024,"finding":"In DLBCL, siRNA-mediated knockdown of C1qC in M2 macrophages significantly reduced CD163 expression; co-culture experiments showed that C1qC-expressing M2 macrophages promote tumor cell proliferation and reduce drug sensitivity, indicating a role for C1qC in sustaining M2 macrophage identity and tumor-promoting macrophage-lymphoma crosstalk.","method":"siRNA knockdown, Western blot, qPCR, co-culture proliferation assay, drug sensitivity assay, single-cell sequencing","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2-3 — loss-of-function with mechanistic readout in co-culture, single lab","pmids":["39388888"],"is_preprint":false}],"current_model":"C1QC encodes the C-chain of the C1q heterotrimer (with A and B chains), whose genes are arranged in tandem on chromosome 1p; the globular head domain of the heterotrimer (including C1QC) mediates versatile ligand recognition—binding IgG (via CH2 ionic contacts), CRP, PTX3, phosphatidylserine on apoptotic cells, and HIV-1 gp41—thereby initiating the classical complement cascade through C1r2s2 activation upon conformational rearrangement; outside the complement cascade, C1QC (as part of C1q) binds plasmacytoid dendritic cells to suppress IFN-α production, and evidence from in vitro/in vivo models indicates that overexpressed C1QC can engage DDR2→MMP9 signaling to disrupt the blood-brain barrier, promote tubular lipid deposition and inflammation in diabetic kidney disease (countered by empagliflozin), sustain M2 macrophage identity and immunosuppression in tumor microenvironments, and participate in neuroinflammatory complement signaling (C1qc→C3/C5aR) downstream of the circDnajc1/miR-27a-5p axis in ischemic stroke."},"narrative":{"teleology":[{"year":1979,"claim":"Determining the primary sequence of the C1QC collagen-like region revealed a Gly→Ala substitution at position C-36 that breaks the Gly-X-Y repeat, providing a structural explanation for the bend observed in electron micrographs of C1q stalks.","evidence":"Direct amino acid sequencing of the purified C-chain collagen-like fragment","pmids":["486087"],"confidence":"High","gaps":["Full-length C-chain sequence not yet available","Three-dimensional structure of the collagen stalk unresolved"]},{"year":1991,"claim":"Cloning and sequencing the complete C1QC gene established the tandem A-C-B gene arrangement on chromosome 1p and defined the full-length C-chain amino acid sequence, completing the molecular characterization of all three C1q subunits.","evidence":"cDNA cloning, cosmid library screening, and genomic DNA sequencing","pmids":["1706597"],"confidence":"High","gaps":["Promoter regulation of the C1QC locus undefined","No structure of the globular head domain"]},{"year":1991,"claim":"Identification of direct, antibody-independent binding between HIV-1 gp41 and C1q demonstrated that C1q can be activated by non-immunoglobulin ligands, broadening its recognized recognition repertoire.","evidence":"Radiolabeled C1q binding, gel exclusion chromatography, and synthetic peptide competition using gp41 fragments","pmids":["1744579"],"confidence":"High","gaps":["Structural basis for gp41-C1q interaction unknown","In vivo relevance during HIV infection not established"]},{"year":2003,"claim":"The 1.9 Å crystal structure of the gC1q heterotrimeric head domain (A, B, C chains) resolved how non-polar interactions and a Ca²⁺ ion stabilize the trimer, and the concurrent demonstration that this domain binds pentraxin PTX3 to activate or inhibit complement depending on context answered how C1q engages pattern-recognition ligands beyond immunoglobulins.","evidence":"X-ray crystallography at 1.9 Å; recombinant globular head binding assays and C4 deposition complement activation assay","pmids":["12960167","12645945"],"confidence":"High","gaps":["Atomic-level models of C1q bound to full-length IgG or CRP not yet available","Mechanism of PTX3 inhibition of C1q–IgG interaction unresolved"]},{"year":2006,"claim":"Site-directed mutagenesis of the globular head C-chain module identified specific charged apex residues critical for binding IgG1, CRP, and PTX3, establishing that multiple ligands share an overlapping ionic interaction surface rather than discrete binding sites.","evidence":"Recombinant globular head modules with point mutations; ELISA and SPR binding assays","pmids":["16566583"],"confidence":"High","gaps":["Relative contribution of each chain to binding affinity for each ligand not fully quantified","Intact C1q context may modify individual head module behavior"]},{"year":2008,"claim":"Demonstration that C1q's globular domain binds phosphatidylserine on apoptotic cell membranes with nanomolar affinity, confirmed by crystallography and SPR, established C1q as a direct sensor of 'eat-me' signals linking complement to apoptotic clearance.","evidence":"SPR, cosedimentation, X-ray crystallography of gC1q–PS complex, confocal microscopy with annexin V competition","pmids":["18250442"],"confidence":"High","gaps":["Relative importance of PS recognition versus opsonin bridging in vivo unclear","Whether individual chains contribute differently to PS binding undefined"]},{"year":2009,"claim":"Binding of C1q to plasmacytoid dendritic cells and suppression of IFN-α production revealed a complement-independent immunoregulatory role for C1q, linking C1q deficiency to the type I IFN signature in SLE.","evidence":"SPR and flow cytometry for binding; cytokine immunoassay after CpG/immune complex stimulation of purified PDCs","pmids":["19790049"],"confidence":"High","gaps":["Receptor on PDCs mediating C1q binding not identified","Whether this function requires heterotrimeric C1q or individual chains unknown"]},{"year":2014,"claim":"Structural and functional evidence that IgG hexamers formed via Fc–Fc interactions are the physiological C1q ligand on target surfaces resolved a long-standing question about the stoichiometry of complement activation, showing that engineered Fc–Fc contacts modulate C1 engagement and cell killing.","evidence":"Cryo-EM, native mass spectrometry, engineered IgG mutants, cell-killing assays","pmids":["24626930"],"confidence":"High","gaps":["How different IgG subclass hexamers influence C1q binding geometry unresolved"]},{"year":2018,"claim":"Cryo-EM of the C1–IgG1 hexamer complex revealed how C1q arm condensation upon antibody binding rearranges the C1r₂s₂ proteases, providing the first mechanistic model for signal transduction from ligand recognition to serine protease activation within the C1 complex.","evidence":"Cryo-EM at sub-nanometer resolution with IgG1 mutant functional validation","pmids":["29449492"],"confidence":"High","gaps":["Full atomic model of activated C1r₂s₂ in complex not yet achieved","Whether activation can occur within a single C1 complex or requires trans-activation between complexes debated"]},{"year":2019,"claim":"Identification of compound heterozygous C1QC mutations (Gly34Arg/Arg69X) causing complete C1q deficiency and SLE with cerebral involvement provided definitive human genetic evidence that C1QC loss of function is sufficient for classical pathway failure and lupus susceptibility.","evidence":"ELISA (absent serum C1q), Western blot, DNA and RNA sequencing in a clinical case","pmids":["31357913"],"confidence":"Medium","gaps":["Single family; broader genotype–phenotype spectrum for C1QC mutations underexplored","Cerebral involvement mechanism not molecularly dissected"]},{"year":2024,"claim":"Discovery that C1QC binds DDR2 and activates MMP9 in cerebral microvascular endothelial cells under diabetic conditions, disrupting the blood–brain barrier, identified a complement-independent pathological axis for C1QC in diabetic microangiopathy.","evidence":"siRNA knockdown and overexpression in high-glucose endothelial cell model and diabetic mouse; co-immunoprecipitation for C1QC–DDR2 interaction","pmids":["39531193"],"confidence":"Medium","gaps":["C1QC–DDR2 binding domain not mapped","Single lab; independent replication needed","Whether monomeric C1QC or trimeric C1q engages DDR2 unresolved"]},{"year":2024,"claim":"Functional studies in DLBCL showed that C1QC sustains M2 macrophage identity (CD163 expression) and that C1QC-expressing macrophages promote tumor cell proliferation and chemoresistance, positioning C1QC as a marker and functional mediator of tumor-associated macrophage immunosuppression.","evidence":"siRNA knockdown of C1QC in M2 macrophages, co-culture proliferation and drug sensitivity assays, single-cell RNA-seq","pmids":["39388888"],"confidence":"Medium","gaps":["Downstream signaling from C1QC in macrophages not defined","Whether C1QC acts as secreted ligand or intracellular factor in this context unclear"]},{"year":2025,"claim":"Elucidation of the circDnajc1/miR-27a-5p/C1qc axis in ischemic stroke showed that C1qc upregulation promotes microglial activation and neuroinflammation via C3/C5aR, placing C1qc downstream of a specific non-coding RNA regulatory circuit in cerebral ischemia-reperfusion injury.","evidence":"MCAO/R rat model and OGD/R cell model; RNA immunoprecipitation and luciferase reporter assays for miR-27a-5p–C1qc targeting","pmids":["40483386"],"confidence":"Medium","gaps":["Whether miR-27a-5p regulation of C1qc is conserved in human stroke unknown","Relative contribution of C1qc versus other complement components downstream of circDnajc1 not dissected"]},{"year":2025,"claim":"In diabetic kidney disease, C1QC upregulation in proximal tubular cells promotes lipid accumulation and inflammation; empagliflozin's renoprotective effect is partly mediated through C1QC downregulation, establishing C1QC as a pharmacologically targetable effector in diabetic nephropathy.","evidence":"siRNA knockdown and overexpression with rescue experiments in vitro and in db/db mice; empagliflozin intervention","pmids":["41252098"],"confidence":"Medium","gaps":["Downstream signaling pathway from C1QC in tubular cells not identified","Single lab; mechanism of empagliflozin-mediated C1QC suppression not defined"]},{"year":null,"claim":"Key unresolved questions include: (1) the structural basis for C1QC interactions with non-canonical partners such as DDR2; (2) whether monomeric C1QC or assembled C1q mediates its complement-independent functions in disease contexts; and (3) the transcriptional and post-transcriptional regulatory circuits controlling C1QC expression in macrophages and epithelial cells.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural data for C1QC–DDR2 interaction","Monomeric versus trimeric functionality in disease not resolved","Transcriptional regulation of C1QC incompletely characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[3,4,5,6,7,8,9]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[5]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005576","term_label":"extracellular region","supporting_discovery_ids":[0,3,4,5,6,7,8,9,10]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,4,5,6,7,8,9,10,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,11,12,13,16]}],"complexes":["C1 complex (C1q:C1r2:C1s2)"],"partners":["C1QA","C1QB","DDR2","MMP9","PTX3","CRP"],"other_free_text":[]},"mechanistic_narrative":"C1QC encodes the C-chain of the C1q heterotrimer, which together with the A- and B-chains forms the recognition subunit of the C1 complex that initiates the classical complement cascade. The three C1q chain genes are arranged in tandem (A-C-B) on chromosome 1p; the C-chain contributes a collagen-like stalk with a characteristic Gly-X-Y interruption at position C-36 that introduces the bend seen by electron microscopy, and a globular head domain whose apex harbors charged residues critical for binding IgG, CRP, PTX3, and phosphatidylserine on apoptotic cells [PMID:486087, PMID:12960167, PMID:16566583, PMID:18250442]. Upon engagement of IgG hexamers, the C1q arms condense and induce conformational rearrangement of the C1r₂s₂ proteases, activating the classical pathway [PMID:24626930, PMID:29449492]. Beyond complement activation, C1q suppresses IFN-α production by plasmacytoid dendritic cells [PMID:19790049], and compound heterozygous loss-of-function mutations in C1QC abolish serum C1q, causing classical-pathway deficiency and systemic lupus erythematosus [PMID:31357913]."},"prefetch_data":{"uniprot":{"accession":"P02747","full_name":"Complement C1q subcomponent subunit C","aliases":[],"length_aa":245,"mass_kda":25.8,"function":"Core component of the complement C1 complex, a multiprotein complex that initiates the classical pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system (PubMed:12847249, PubMed:19006321, PubMed:24626930, PubMed:29449492, PubMed:3258649, PubMed:34155115, PubMed:6249812, PubMed:6776418). The classical complement pathway is initiated by the C1Q subcomplex of the C1 complex, which specifically binds IgG or IgM immunoglobulins complexed with antigens, forming antigen-antibody complexes on the surface of pathogens: C1QA, together with C1QB and C1QC, specifically recognizes and binds the Fc regions of IgG or IgM via its C1q domain (PubMed:12847249, PubMed:19006321, PubMed:24626930, PubMed:29449492, PubMed:3258649, PubMed:6776418). Immunoglobulin-binding activates the proenzyme C1R, which cleaves C1S, initiating the proteolytic cascade of the complement system (PubMed:29449492). The C1Q subcomplex is activated by a hexamer of IgG complexed with antigens, while it is activated by a pentameric IgM (PubMed:19706439, PubMed:24626930, PubMed:29449492). The C1Q subcomplex also recognizes and binds phosphatidylserine exposed on the surface of cells undergoing programmed cell death, possibly promoting activation of the complement system (PubMed:18250442)","subcellular_location":"Secreted; Cell surface","url":"https://www.uniprot.org/uniprotkb/P02747/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C1QC","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/C1QC","total_profiled":1310},"omim":[{"mim_id":"620322","title":"C1q DEFICIENCY 3; C1QD3","url":"https://www.omim.org/entry/620322"},{"mim_id":"613652","title":"C1q DEFICIENCY 1; C1QD1","url":"https://www.omim.org/entry/613652"},{"mim_id":"120575","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT, C CHAIN; C1QC","url":"https://www.omim.org/entry/120575"},{"mim_id":"120550","title":"COMPLEMENT COMPONENT 1, q SUBCOMPONENT, A CHAIN; C1QA","url":"https://www.omim.org/entry/120550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":893.4}],"url":"https://www.proteinatlas.org/search/C1QC"},"hgnc":{"alias_symbol":[],"prev_symbol":["C1QG"]},"alphafold":{"accession":"P02747","domains":[{"cath_id":"2.60.120.40","chopping":"117-243","consensus_level":"high","plddt":96.1127,"start":117,"end":243}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P02747","model_url":"https://alphafold.ebi.ac.uk/files/AF-P02747-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P02747-F1-predicted_aligned_error_v6.png","plddt_mean":80.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C1QC","jax_strain_url":"https://www.jax.org/strain/search?query=C1QC"},"sequence":{"accession":"P02747","fasta_url":"https://rest.uniprot.org/uniprotkb/P02747.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P02747/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P02747"}},"corpus_meta":[{"pmid":"34295336","id":"PMC_34295336","title":"Multi-Omics Analysis Showed the Clinical Value of Gene Signatures of C1QC+ and SPP1+ TAMs in Cervical Cancer.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34295336","citation_count":45,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31019999","id":"PMC_31019999","title":"C1QA and C1QC modify age-at-onset in familial amyloid polyneuropathy patients.","date":"2019","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31019999","citation_count":15,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40740771","id":"PMC_40740771","title":"Identification of a stromal immunosuppressive barrier orchestrated by SPP1+/C1QC+ macrophages and CD8+ exhausted T cells driving gastric cancer immunotherapy resistance.","date":"2025","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/40740771","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36644582","id":"PMC_36644582","title":"C1QC, VSIG4, and CFD as Potential Peripheral Blood Biomarkers in Atrial Fibrillation-Related Cardioembolic Stroke.","date":"2023","source":"Oxidative medicine and cellular longevity","url":"https://pubmed.ncbi.nlm.nih.gov/36644582","citation_count":9,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39388888","id":"PMC_39388888","title":"Single-cell sequencing in diffuse large B-cell lymphoma: C1qC is a potential tumor-promoting factor.","date":"2024","source":"International immunopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/39388888","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"31357913","id":"PMC_31357913","title":"Complex medical history of a patient with a compound heterozygous mutation in C1QC.","date":"2019","source":"Lupus","url":"https://pubmed.ncbi.nlm.nih.gov/31357913","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39626448","id":"PMC_39626448","title":"Exploring the mechanism of Taohong Siwu 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circulating C1q complex formation and classical complement pathway activation.\",\n      \"method\": \"ELISA, Western blot for C1q protein detection; DNA sequencing and RNA sequencing to identify and confirm compound heterozygous mutations on different chromosomes\",\n      \"journal\": \"Lupus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct loss-of-function (genetic deficiency) with defined biochemical phenotype (absent C1q), single case report\",\n      \"pmids\": [\"31357913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Under diabetic conditions, C1QC binds to discoidin domain receptor 2 (DDR2), triggering downstream activation of MMP9, a calcium-dependent extracellular matrix-degrading enzyme, leading to structural and functional disruption of the blood-brain barrier; siRNA-mediated C1QC suppression mitigated BBB damage.\",\n      \"method\": \"Bioinformatics-identified C1QC upregulation validated in in vivo diabetic mouse model and in vitro endothelial cell model; C1QC knockdown experiments; binding partner identified as DDR2 with downstream MMP9 activation\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — in vivo and in vitro loss-of-function with defined pathway (C1QC→DDR2→MMP9→BBB disruption), single lab, moderate mechanistic depth\",\n      \"pmids\": [\"39531193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In a rat ischemic stroke model (MCAO/R), circDnajc1 acts as a sponge for miR-27a-5p, relieving repression of C1qc; elevated C1qc in turn upregulates C3 and C5aR expression, promotes microglial activation, inflammatory factor release, and neuronal apoptosis. circDnajc1 knockdown reversed these effects.\",\n      \"method\": \"MCAO/R rat model and OGD/R in vitro model; siRNA knockdown and overexpression of circDnajc1; RNA immunoprecipitation and luciferase reporter assays validating circDnajc1/miR-27a-5p/C1qc axis; RT-qPCR, Western blot, immunofluorescence\",\n      \"journal\": \"Phytomedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (RIP, luciferase, KD/OE) in both in vivo and in vitro models; single lab\",\n      \"pmids\": [\"39626448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"circDnajc1 promotes microglial activation in ischemic stroke by acting as a ceRNA for miR-27a-5p, leading to upregulation of C1qc, C3, and C5ar; circDnajc1 knockdown suppressed C1qc expression, inhibited microglial activation, reduced inflammatory cytokine release, and protected neurons from apoptosis in MCAO/R rats.\",\n      \"method\": \"MCAO/R rat model and OGD/R neuron-microglia co-culture; flow cytometry, RT-qPCR, immunofluorescence, RNA immunoprecipitation, luciferase reporter gene assays; circDnajc1 siRNA and overexpression vectors\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods replicating and extending the circDnajc1/miR-27a-5p/C1qc axis finding from the same research group\",\n      \"pmids\": [\"40483386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In diabetic kidney disease, high glucose and palmitate induce C1QC overexpression in proximal tubular cells; siRNA-mediated C1QC silencing attenuates lipid accumulation and inflammation, whereas C1QC overexpression exacerbates these pathologies; the SGLT2 inhibitor empagliflozin reduces renal C1QC expression and confers renoprotection, which is partially reversed by C1QC overexpression.\",\n      \"method\": \"siRNA knockdown and plasmid overexpression of C1QC in HK-2 cells challenged with high glucose/palmitate; in vivo db/db mouse model treated with empagliflozin; rescue experiments combining empagliflozin with C1QC overexpression\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — both in vitro and in vivo gain/loss-of-function with defined phenotypic readouts (lipid deposition, inflammation), rescue experiment; single lab\",\n      \"pmids\": [\"41252098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In DLBCL, C1qC is highly expressed in M2 macrophages; siRNA-mediated knockdown of C1qC significantly reduces CD163 expression (M2 marker); co-culture experiments show that C1qC-expressing M2 macrophages promote tumor cell proliferation and reduce drug sensitivity; C1qC expression positively correlates with immune checkpoint molecules and infiltration of Tregs and M2 macrophages.\",\n      \"method\": \"Single-cell sequencing; siRNA knockdown of C1qC in macrophages with Western blot and qPCR for M2 markers; tumor cell-macrophage co-culture proliferation and drug sensitivity assays; multiplex IHC\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss-of-function with specific molecular and functional readouts in co-culture; single lab with multiple methods\",\n      \"pmids\": [\"39388888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"FAP+ cancer-associated fibroblasts secrete WNT2 to activate β-catenin signaling in macrophages, upregulating C1QC and M2 markers; C1QC+ macrophages then secrete CCL2 to recruit Tregs and induce T cell exhaustion; inhibition of FAP reduces C1QC+ macrophage infiltration; this FAP-WNT2-C1QC axis mediates immunosuppression in OSCC.\",\n      \"method\": \"scRNA-seq, spatial transcriptomics, in vitro co-culture systems, in vivo OSCC animal model with FAP inhibition; multi-omics analyses of stromal-immune crosstalk; anti-PD-1 treatment experiments\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (scRNA-seq, spatial transcriptomics, in vitro and in vivo functional assays) establishing the WNT2→β-catenin→C1QC pathway; single lab\",\n      \"pmids\": [\"41831519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"C1QC+ macrophages drive CD8+ T cell exhaustion through pregnenolone synthesis via the steroidogenic enzyme CYP11A1, identifying pregnenolone metabolism as an immunosuppressive mechanism downstream of C1QC+ macrophage activity in BRAF mutant colorectal cancer.\",\n      \"method\": \"High-resolution spatial analysis and single-cell RNA sequencing mapping TME; mechanistic link between C1QC+ macrophages and CYP11A1-mediated pregnenolone synthesis identified\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3-4 — preprint, primarily transcriptomic/spatial analysis; CYP11A1 mechanistic link inferred rather than directly tested with functional perturbation\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"C1QC encodes a subunit of the complement C1q complex essential for classical complement pathway activation; loss-of-function mutations abolish serum C1q and cause immunodeficiency/SLE. Beyond its structural complement role, C1QC can bind DDR2 to activate MMP9 and disrupt the blood-brain barrier, is regulated post-transcriptionally via the circDnajc1/miR-27a-5p axis to promote microglial activation and neuroinflammation, drives lipid accumulation and inflammation in renal tubular cells under metabolic stress, and when expressed by M2/C1QC+ tumor-associated macrophages, promotes immunosuppression through CCL2-mediated Treg recruitment, T cell exhaustion, and (in one proposed mechanism) pregnenolone biosynthesis.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Crystal structure of the C1q globular domain resolved to 1.9 Å reveals a compact heterotrimeric assembly (comprising the C-terminal globular regions of the A, B, and C chains, including C1QC) held together mainly by non-polar interactions with a Ca2+ ion bound at the top; structural models suggest this heterotrimeric arrangement underlies C1q's versatile ligand-recognition properties and indicates plausible binding modes for CRP and IgG.\",\n      \"method\": \"X-ray crystallography at 1.9 Å resolution\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional modeling, foundational paper with >280 citations\",\n      \"pmids\": [\"12960167\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The genes encoding the A, B, and C chains of human C1q (including C1QC) are arranged in tandem (5'→3' order A-C-B) on a 24 kb stretch of chromosome 1p; the C-chain gene is ~3.2 kb with one intron located within a codon for a glycine residue in the collagen-like region; the complete derived amino acid sequence of C1QC was determined, completing the full C1q sequence.\",\n      \"method\": \"cDNA cloning, cosmid library isolation, DNA sequencing, Southern blot\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct sequencing and genomic characterization, foundational paper with >190 citations\",\n      \"pmids\": [\"1706597\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1979,\n      \"finding\": \"The complete amino acid sequence of the collagen-like region of the C1q C-chain (C1QC) was determined, revealing that continuity of the Gly-X-Y repeating triplet is broken at position C-36 where alanine replaces glycine, a feature shared with the B-chain, suggesting a structural basis for the bending observed in electron microscopy of C1q.\",\n      \"method\": \"Amino acid sequencing\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct protein sequencing, foundational paper with >110 citations\",\n      \"pmids\": [\"486087\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mutational analysis of recombinant globular head modules of the C1q C chain (ghC) demonstrated that charged residues at the apex of the heterotrimeric gC1q domain (involving all three chains, including ghC) are critical for binding to IgG1, CRP, and PTX3; contribution of each chain differs per ligand, suggesting a shared ionic/hydrogen-bond interaction surface rather than separate discrete binding sites.\",\n      \"method\": \"Recombinant globular head module expression, site-directed mutagenesis, binding assays (ELISA/SPR)\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis combined with functional binding assays, >120 citations\",\n      \"pmids\": [\"16566583\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Experiments with recombinant globular head domains of C1q A, B, and C chains showed that the C1q globular head region (including the C-chain/C1QC) mediates binding to pentraxin 3 (PTX3); PTX3 bound to immobilized C1q activates the classical complement pathway (C4 deposition), whereas fluid-phase PTX3-C1q complexes inhibit complement activation by blocking C1q-immunoglobulin interaction.\",\n      \"method\": \"Recombinant globular head domain binding assays, C4 deposition assay, dose-response experiments\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstitution and functional complement assays, >280 citations\",\n      \"pmids\": [\"12645945\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"C1q binds phosphatidylserine (PS) on apoptotic cells through its globular domain (the heterotrimer including C1QC); X-ray crystallography confirmed direct C1q globular domain–PS interaction, with KD = 3.7–7×10⁻⁸ M via interactions with the phosphoserine group; confocal microscopy showed C1q colocalizes with PS in membrane patches at early stages of apoptosis.\",\n      \"method\": \"Surface plasmon resonance, cosedimentation, X-ray crystallography, confocal microscopy, annexin V competition assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — multiple orthogonal methods including crystallography and SPR, >220 citations\",\n      \"pmids\": [\"18250442\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IgG hexamers formed via noncovalent Fc-Fc interactions after antigen binding recruit and activate the C1 complex (containing C1QC as part of the C1q heterotrimer); manipulation of Fc-Fc interactions modulated complement activation and target cell killing across all four IgG subclasses, providing a model for antibody-mediated complement activation.\",\n      \"method\": \"Cryo-EM, native mass spectrometry, cell-killing assays, engineered IgG mutants\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — structural and functional reconstitution with mutagenesis, >630 citations\",\n      \"pmids\": [\"24626930\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structures of C1 bound to IgG1 hexamers revealed distinct C1q binding sites on both Fc-CH2 domains of each IgG molecule; upon antibody binding, C1q arms condense, inducing rearrangement of C1r2s2 proteases and tilting C1q's cone-shaped stalk, suggesting C1r activation of C1s can occur within single strained C1 complexes or between neighboring complexes on surfaces.\",\n      \"method\": \"Cryo-electron microscopy, IgG1 mutant functional analysis\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM with mutant validation, >140 citations\",\n      \"pmids\": [\"29449492\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"HIV-1 gp41 directly binds C1q (but not C1s dimers), and synthetic peptides spanning positions 591–605 and 601–620 of gp160 mediate both C1q binding and C1 complex activation leading to C3 deposition; this identifies specific sites in gp41 that engage C1 (containing C1QC) independent of antibody.\",\n      \"method\": \"Gel exclusion chromatography, radiolabeled C1q binding, recombinant protein binding assay, synthetic peptide competition\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reconstituted binding and activation assays with peptide mapping, >185 citations\",\n      \"pmids\": [\"1744579\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"C1q (the heterotrimer including C1QC) binds to plasmacytoid dendritic cells (PDCs) as demonstrated by surface plasmon resonance and flow cytometry, and inhibits immune complex- and CpG-induced IFN-α production by PDCs; this regulatory function links C1q deficiency to the type I IFN upregulation characteristic of SLE pathogenesis.\",\n      \"method\": \"Surface plasmon resonance, flow cytometry, cytokine immunoassay, PBMC/PDC stimulation assays\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal binding plus functional cytokine readout, >145 citations\",\n      \"pmids\": [\"19790049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A compound heterozygous mutation in C1QC (c.100G>A p.Gly34Arg and c.205C>T p.Arg69X on different chromosomes confirmed by RNA sequencing) results in complete absence of C1q protein in serum, causing classical-pathway complement deficiency and associated SLE with cerebral involvement.\",\n      \"method\": \"ELISA, Western blot, DNA sequencing, RNA sequencing\",\n      \"journal\": \"Lupus\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function genotype confirmed by protein-level assays in a clinical case\",\n      \"pmids\": [\"31357913\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Under diabetic conditions, C1QC is upregulated in cerebral microvascular endothelial cells; C1QC binds to discoidin domain receptor 2 (DDR2) and activates downstream MMP9, a calcium-dependent matrix metalloprotease that degrades extracellular matrix components, leading to structural and functional disruption of the blood-brain barrier; siRNA-mediated C1QC suppression mitigated BBB damage in vitro and in vivo.\",\n      \"method\": \"Bioinformatics, in vivo diabetic mouse model, in vitro high-glucose cell model, siRNA knockdown, Western blot, co-immunoprecipitation/binding assay\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD with defined molecular pathway (C1QC→DDR2→MMP9→BBB disruption), single lab\",\n      \"pmids\": [\"39531193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In diabetic kidney disease, C1QC is upregulated in proximal tubular cells under high glucose/palmitate stress; C1QC knockdown attenuates lipid accumulation and inflammation whereas C1QC overexpression exacerbates them; the SGLT2 inhibitor empagliflozin confers renoprotection partly by downregulating C1QC, and C1QC overexpression partially reverses empagliflozin's protective effects in vitro and in db/db mice.\",\n      \"method\": \"siRNA knockdown, plasmid overexpression, empagliflozin pharmacological intervention, in vivo db/db mouse model, rescue experiments\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — gain/loss-of-function with rescue in both in vitro and in vivo models, single lab\",\n      \"pmids\": [\"41252098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In ischemic stroke (MCAO/R model), circDnajc1 acts as a sponge for miR-27a-5p, relieving miR-27a-5p-mediated suppression of C1qc; elevated C1qc promotes microglial activation, upregulates C3 and C5aR, drives inflammatory factor release and neuronal apoptosis; circDnajc1 knockdown inhibits microglial activation and is neuroprotective through this axis; validated by RNA immunoprecipitation and luciferase reporter assays.\",\n      \"method\": \"MCAO/R rat model, OGD/R cell model, siRNA/overexpression, RT-qPCR, immunofluorescence, flow cytometry, RNA immunoprecipitation, luciferase reporter assay\",\n      \"journal\": \"Molecular neurobiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — pathway placement via RIP and luciferase assays with in vivo validation, single lab\",\n      \"pmids\": [\"40483386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In grass carp, recombinant C1qC protein (rC1qC) exerts a substantial inhibitory effect on grass carp reovirus (GCRV) replication in CIK cells after 24 h of GCRV inoculation, demonstrating direct antiviral activity for the C1qC protein in a teleost model.\",\n      \"method\": \"Recombinant protein incubation assay, viral replication quantification in cell culture\",\n      \"journal\": \"Fish & shellfish immunology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method in non-mammalian organism (fish ortholog), single lab\",\n      \"pmids\": [\"38447782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FAP+ fibroblasts secrete WNT2 to activate β-catenin signaling in macrophages, upregulating C1QC and M2 markers; C1QC+ macrophages then exhibit enhanced fatty acid metabolism, secrete CCL2 to recruit Tregs, and induce T cell exhaustion; inhibition of FAP reshaped the immune landscape by reducing C1QC+ macrophage infiltration.\",\n      \"method\": \"scRNA-seq, spatial transcriptomics, co-culture systems, in vivo OSCC mouse model, FAP inhibition, multi-omics\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — WNT2→β-catenin→C1QC axis defined by co-culture and in vivo experiments, single lab\",\n      \"pmids\": [\"41831519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In DLBCL, siRNA-mediated knockdown of C1qC in M2 macrophages significantly reduced CD163 expression; co-culture experiments showed that C1qC-expressing M2 macrophages promote tumor cell proliferation and reduce drug sensitivity, indicating a role for C1qC in sustaining M2 macrophage identity and tumor-promoting macrophage-lymphoma crosstalk.\",\n      \"method\": \"siRNA knockdown, Western blot, qPCR, co-culture proliferation assay, drug sensitivity assay, single-cell sequencing\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — loss-of-function with mechanistic readout in co-culture, single lab\",\n      \"pmids\": [\"39388888\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C1QC encodes the C-chain of the C1q heterotrimer (with A and B chains), whose genes are arranged in tandem on chromosome 1p; the globular head domain of the heterotrimer (including C1QC) mediates versatile ligand recognition—binding IgG (via CH2 ionic contacts), CRP, PTX3, phosphatidylserine on apoptotic cells, and HIV-1 gp41—thereby initiating the classical complement cascade through C1r2s2 activation upon conformational rearrangement; outside the complement cascade, C1QC (as part of C1q) binds plasmacytoid dendritic cells to suppress IFN-α production, and evidence from in vitro/in vivo models indicates that overexpressed C1QC can engage DDR2→MMP9 signaling to disrupt the blood-brain barrier, promote tubular lipid deposition and inflammation in diabetic kidney disease (countered by empagliflozin), sustain M2 macrophage identity and immunosuppression in tumor microenvironments, and participate in neuroinflammatory complement signaling (C1qc→C3/C5aR) downstream of the circDnajc1/miR-27a-5p axis in ischemic stroke.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"C1QC encodes the C chain of complement component C1q, a subunit essential for assembly of the circulating C1q heterotrimer and activation of the classical complement pathway; compound heterozygous loss-of-function mutations in C1QC abolish serum C1q and cause complement deficiency [PMID:31357913]. Beyond its canonical complement role, C1QC functions as a ligand for discoidin domain receptor 2 (DDR2), activating MMP9 and promoting blood–brain barrier disruption under diabetic conditions [PMID:39531193], and its expression in renal tubular cells under metabolic stress drives lipid accumulation and inflammation [PMID:41252098]. C1QC is post-transcriptionally regulated via the circDnajc1/miR-27a-5p axis to promote microglial activation and neuroinflammation through downstream C3/C5aR signaling [PMID:39626448]. In the tumor microenvironment, C1QC marks immunosuppressive M2-polarized tumor-associated macrophages whose WNT2/β-catenin–driven C1QC expression enables CCL2-mediated Treg recruitment and CD8+ T cell exhaustion [PMID:41831519, PMID:39388888].\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Establishing that C1QC is indispensable for circulating C1q complex assembly resolved the question of whether individual C1q chain mutations suffice to ablate the entire heterotrimer and classical pathway function.\",\n      \"evidence\": \"Compound heterozygous C1QC mutations identified by DNA/RNA sequencing in a patient with absent serum C1q by ELISA and Western blot\",\n      \"pmids\": [\"31357913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single case report; independent families with distinct C1QC mutations not yet reported\",\n        \"Whether the missense p.Gly34Arg alone (without the nonsense allele) partially impairs C1q assembly is untested\",\n        \"No structural data on how C chain loss prevents A/B chain incorporation into the heterotrimer\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying DDR2 as a direct binding partner of C1QC and MMP9 as its downstream effector established a complement-independent, non-immune signaling axis through which C1QC damages the blood–brain barrier in diabetes.\",\n      \"evidence\": \"C1QC–DDR2 interaction characterized in diabetic mouse brain and endothelial cells; siRNA knockdown of C1QC rescued BBB integrity\",\n      \"pmids\": [\"39531193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct biophysical evidence for C1QC–DDR2 binding (e.g., co-IP, SPR) not described in detail\",\n        \"Whether C1QC acts as monomeric chain or within intact C1q for DDR2 engagement is unknown\",\n        \"Generalizability beyond diabetic BBB pathology not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Delineating the circDnajc1/miR-27a-5p/C1qc ceRNA axis answered how C1qc is post-transcriptionally upregulated during ischemic stroke and linked C1qc to microglial activation, complement amplification (C3/C5aR), and neuronal apoptosis.\",\n      \"evidence\": \"RNA immunoprecipitation, luciferase reporters, and siRNA/overexpression in MCAO/R rat and OGD/R in vitro models across two related studies\",\n      \"pmids\": [\"39626448\", \"40483386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Both studies from the same research group; independent replication needed\",\n        \"Whether C1qc upregulation acts through classical complement activation or a distinct mechanism in microglia is unresolved\",\n        \"Relevance of circDnajc1/miR-27a-5p axis to human ischemic stroke not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrating that C1QC knockdown in macrophages reduces M2 polarization markers and that C1QC+ macrophages promote tumor proliferation and drug resistance established C1QC as a functional effector of immunosuppressive macrophage activity in lymphoma.\",\n      \"evidence\": \"siRNA knockdown in macrophages with co-culture proliferation and drug sensitivity assays in DLBCL; multiplex IHC and single-cell sequencing\",\n      \"pmids\": [\"39388888\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which C1QC sustains M2 polarization is not defined\",\n        \"Whether C1QC is causally required for Treg recruitment or merely correlative in this system is untested\",\n        \"Single tumor type examined\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Showing that metabolic stress induces C1QC in renal tubular cells and that C1QC gain/loss of function modulates lipid accumulation and inflammation—and that empagliflozin's renoprotection is partially C1QC-dependent—placed C1QC in metabolic kidney disease pathogenesis.\",\n      \"evidence\": \"siRNA and overexpression in HK-2 cells with high glucose/palmitate; db/db mice treated with empagliflozin; rescue experiments\",\n      \"pmids\": [\"41252098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Downstream signaling pathway connecting C1QC to lipid accumulation in tubular cells is uncharacterized\",\n        \"Whether C1QC acts via complement activation or a non-canonical mechanism in kidney is unclear\",\n        \"Single lab, single model system\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Mapping the FAP→WNT2→β-catenin→C1QC signaling cascade in CAF–macrophage crosstalk, with C1QC+ macrophages secreting CCL2 to recruit Tregs and exhaust T cells, revealed the upstream transcriptional control and downstream immunosuppressive effector mechanism of C1QC in the tumor microenvironment.\",\n      \"evidence\": \"scRNA-seq, spatial transcriptomics, in vitro co-culture, and in vivo FAP inhibition in OSCC models\",\n      \"pmids\": [\"41831519\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether β-catenin directly transactivates C1QC or acts through intermediate factors is not resolved\",\n        \"Functional perturbation of C1QC itself (rather than upstream FAP/WNT2) was not reported\",\n        \"Applicability across tumor types beyond OSCC not established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include whether C1QC's non-complement functions (DDR2 signaling, macrophage polarization, metabolic stress responses) require the intact C1q heterotrimer or operate through monomeric/homomeric C chain species, and what the direct transcriptional targets and signaling outputs of C1QC are in non-immune cells.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural or biophysical data on C1QC outside the C1q complex\",\n        \"No genome-wide perturbation screen defining C1QC-dependent transcriptional or signaling programs\",\n        \"Relationship between complement-dependent and complement-independent C1QC functions remains undefined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 3, 5, 6]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 4, 5, 6]}\n    ],\n    \"complexes\": [\n      \"C1q complex\"\n    ],\n    \"partners\": [\n      \"C1QA\",\n      \"C1QB\",\n      \"DDR2\",\n      \"MMP9\",\n      \"CCL2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"C1QC encodes the C-chain of the C1q heterotrimer, which together with the A- and B-chains forms the recognition subunit of the C1 complex that initiates the classical complement cascade. The three C1q chain genes are arranged in tandem (A-C-B) on chromosome 1p; the C-chain contributes a collagen-like stalk with a characteristic Gly-X-Y interruption at position C-36 that introduces the bend seen by electron microscopy, and a globular head domain whose apex harbors charged residues critical for binding IgG, CRP, PTX3, and phosphatidylserine on apoptotic cells [PMID:486087, PMID:12960167, PMID:16566583, PMID:18250442]. Upon engagement of IgG hexamers, the C1q arms condense and induce conformational rearrangement of the C1r₂s₂ proteases, activating the classical pathway [PMID:24626930, PMID:29449492]. Beyond complement activation, C1q suppresses IFN-α production by plasmacytoid dendritic cells [PMID:19790049], and compound heterozygous loss-of-function mutations in C1QC abolish serum C1q, causing classical-pathway deficiency and systemic lupus erythematosus [PMID:31357913].\",\n  \"teleology\": [\n    {\n      \"year\": 1979,\n      \"claim\": \"Determining the primary sequence of the C1QC collagen-like region revealed a Gly→Ala substitution at position C-36 that breaks the Gly-X-Y repeat, providing a structural explanation for the bend observed in electron micrographs of C1q stalks.\",\n      \"evidence\": \"Direct amino acid sequencing of the purified C-chain collagen-like fragment\",\n      \"pmids\": [\"486087\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length C-chain sequence not yet available\", \"Three-dimensional structure of the collagen stalk unresolved\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Cloning and sequencing the complete C1QC gene established the tandem A-C-B gene arrangement on chromosome 1p and defined the full-length C-chain amino acid sequence, completing the molecular characterization of all three C1q subunits.\",\n      \"evidence\": \"cDNA cloning, cosmid library screening, and genomic DNA sequencing\",\n      \"pmids\": [\"1706597\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Promoter regulation of the C1QC locus undefined\", \"No structure of the globular head domain\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Identification of direct, antibody-independent binding between HIV-1 gp41 and C1q demonstrated that C1q can be activated by non-immunoglobulin ligands, broadening its recognized recognition repertoire.\",\n      \"evidence\": \"Radiolabeled C1q binding, gel exclusion chromatography, and synthetic peptide competition using gp41 fragments\",\n      \"pmids\": [\"1744579\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for gp41-C1q interaction unknown\", \"In vivo relevance during HIV infection not established\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"The 1.9 Å crystal structure of the gC1q heterotrimeric head domain (A, B, C chains) resolved how non-polar interactions and a Ca²⁺ ion stabilize the trimer, and the concurrent demonstration that this domain binds pentraxin PTX3 to activate or inhibit complement depending on context answered how C1q engages pattern-recognition ligands beyond immunoglobulins.\",\n      \"evidence\": \"X-ray crystallography at 1.9 Å; recombinant globular head binding assays and C4 deposition complement activation assay\",\n      \"pmids\": [\"12960167\", \"12645945\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-level models of C1q bound to full-length IgG or CRP not yet available\", \"Mechanism of PTX3 inhibition of C1q–IgG interaction unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Site-directed mutagenesis of the globular head C-chain module identified specific charged apex residues critical for binding IgG1, CRP, and PTX3, establishing that multiple ligands share an overlapping ionic interaction surface rather than discrete binding sites.\",\n      \"evidence\": \"Recombinant globular head modules with point mutations; ELISA and SPR binding assays\",\n      \"pmids\": [\"16566583\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each chain to binding affinity for each ligand not fully quantified\", \"Intact C1q context may modify individual head module behavior\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstration that C1q's globular domain binds phosphatidylserine on apoptotic cell membranes with nanomolar affinity, confirmed by crystallography and SPR, established C1q as a direct sensor of 'eat-me' signals linking complement to apoptotic clearance.\",\n      \"evidence\": \"SPR, cosedimentation, X-ray crystallography of gC1q–PS complex, confocal microscopy with annexin V competition\",\n      \"pmids\": [\"18250442\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative importance of PS recognition versus opsonin bridging in vivo unclear\", \"Whether individual chains contribute differently to PS binding undefined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Binding of C1q to plasmacytoid dendritic cells and suppression of IFN-α production revealed a complement-independent immunoregulatory role for C1q, linking C1q deficiency to the type I IFN signature in SLE.\",\n      \"evidence\": \"SPR and flow cytometry for binding; cytokine immunoassay after CpG/immune complex stimulation of purified PDCs\",\n      \"pmids\": [\"19790049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Receptor on PDCs mediating C1q binding not identified\", \"Whether this function requires heterotrimeric C1q or individual chains unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Structural and functional evidence that IgG hexamers formed via Fc–Fc interactions are the physiological C1q ligand on target surfaces resolved a long-standing question about the stoichiometry of complement activation, showing that engineered Fc–Fc contacts modulate C1 engagement and cell killing.\",\n      \"evidence\": \"Cryo-EM, native mass spectrometry, engineered IgG mutants, cell-killing assays\",\n      \"pmids\": [\"24626930\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How different IgG subclass hexamers influence C1q binding geometry unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Cryo-EM of the C1–IgG1 hexamer complex revealed how C1q arm condensation upon antibody binding rearranges the C1r₂s₂ proteases, providing the first mechanistic model for signal transduction from ligand recognition to serine protease activation within the C1 complex.\",\n      \"evidence\": \"Cryo-EM at sub-nanometer resolution with IgG1 mutant functional validation\",\n      \"pmids\": [\"29449492\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full atomic model of activated C1r₂s₂ in complex not yet achieved\", \"Whether activation can occur within a single C1 complex or requires trans-activation between complexes debated\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of compound heterozygous C1QC mutations (Gly34Arg/Arg69X) causing complete C1q deficiency and SLE with cerebral involvement provided definitive human genetic evidence that C1QC loss of function is sufficient for classical pathway failure and lupus susceptibility.\",\n      \"evidence\": \"ELISA (absent serum C1q), Western blot, DNA and RNA sequencing in a clinical case\",\n      \"pmids\": [\"31357913\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family; broader genotype–phenotype spectrum for C1QC mutations underexplored\", \"Cerebral involvement mechanism not molecularly dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that C1QC binds DDR2 and activates MMP9 in cerebral microvascular endothelial cells under diabetic conditions, disrupting the blood–brain barrier, identified a complement-independent pathological axis for C1QC in diabetic microangiopathy.\",\n      \"evidence\": \"siRNA knockdown and overexpression in high-glucose endothelial cell model and diabetic mouse; co-immunoprecipitation for C1QC–DDR2 interaction\",\n      \"pmids\": [\"39531193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"C1QC–DDR2 binding domain not mapped\", \"Single lab; independent replication needed\", \"Whether monomeric C1QC or trimeric C1q engages DDR2 unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Functional studies in DLBCL showed that C1QC sustains M2 macrophage identity (CD163 expression) and that C1QC-expressing macrophages promote tumor cell proliferation and chemoresistance, positioning C1QC as a marker and functional mediator of tumor-associated macrophage immunosuppression.\",\n      \"evidence\": \"siRNA knockdown of C1QC in M2 macrophages, co-culture proliferation and drug sensitivity assays, single-cell RNA-seq\",\n      \"pmids\": [\"39388888\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling from C1QC in macrophages not defined\", \"Whether C1QC acts as secreted ligand or intracellular factor in this context unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Elucidation of the circDnajc1/miR-27a-5p/C1qc axis in ischemic stroke showed that C1qc upregulation promotes microglial activation and neuroinflammation via C3/C5aR, placing C1qc downstream of a specific non-coding RNA regulatory circuit in cerebral ischemia-reperfusion injury.\",\n      \"evidence\": \"MCAO/R rat model and OGD/R cell model; RNA immunoprecipitation and luciferase reporter assays for miR-27a-5p–C1qc targeting\",\n      \"pmids\": [\"40483386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether miR-27a-5p regulation of C1qc is conserved in human stroke unknown\", \"Relative contribution of C1qc versus other complement components downstream of circDnajc1 not dissected\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"In diabetic kidney disease, C1QC upregulation in proximal tubular cells promotes lipid accumulation and inflammation; empagliflozin's renoprotective effect is partly mediated through C1QC downregulation, establishing C1QC as a pharmacologically targetable effector in diabetic nephropathy.\",\n      \"evidence\": \"siRNA knockdown and overexpression with rescue experiments in vitro and in db/db mice; empagliflozin intervention\",\n      \"pmids\": [\"41252098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling pathway from C1QC in tubular cells not identified\", \"Single lab; mechanism of empagliflozin-mediated C1QC suppression not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include: (1) the structural basis for C1QC interactions with non-canonical partners such as DDR2; (2) whether monomeric C1QC or assembled C1q mediates its complement-independent functions in disease contexts; and (3) the transcriptional and post-transcriptional regulatory circuits controlling C1QC expression in macrophages and epithelial cells.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural data for C1QC–DDR2 interaction\", \"Monomeric versus trimeric functionality in disease not resolved\", \"Transcriptional regulation of C1QC incompletely characterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [3, 4, 5, 6, 7, 8, 9]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005576\", \"supporting_discovery_ids\": [0, 3, 4, 5, 6, 7, 8, 9, 10]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 4, 5, 6, 7, 8, 9, 10, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 11, 12, 13, 16]}\n    ],\n    \"complexes\": [\n      \"C1 complex (C1q:C1r2:C1s2)\"\n    ],\n    \"partners\": [\n      \"C1QA\",\n      \"C1QB\",\n      \"DDR2\",\n      \"MMP9\",\n      \"PTX3\",\n      \"CRP\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}