{"gene":"C1QBP","run_date":"2026-06-09T22:02:45","timeline":{"discoveries":[{"year":1998,"finding":"p32/gC1qR contains a 33-amino acid N-terminal presequence that functions as a mitochondrial targeting sequence; a fusion protein of this presequence with GFP translocated to mitochondria of transfected COS-7 cells with proteolytic removal of ~6 kDa, and the mature protein resides in the mitochondrial matrix and/or inner membrane.","method":"Confocal laser-scanning microscopy, GFP fusion protein transfection, mitoplast fractionation, immunocytochemistry","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct localization by GFP reporter + colocalization with mitochondrial marker + fractionation, replicated across multiple cell types","pmids":["9531316"],"is_preprint":false},{"year":1996,"finding":"Recombinant gC1qR binds the heparin-binding multimeric form of vitronectin (but not the plasma form) with saturable, high-affinity interaction (KD ~20 nM) inhibitable by glycosaminoglycans; this binding site is distinct from the C1q-binding site, as a truncated gC1qR lacking the N-terminal 22 amino acids lost vitronectin binding but retained C1q binding.","method":"Recombinant protein expression, affinity chromatography with plasma/serum, solid-phase binding assay, inhibition studies with truncation mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with recombinant proteins, mutagenesis (truncation), KD measured, single lab","pmids":["8900153"],"is_preprint":false},{"year":1996,"finding":"gC1qR is a zinc-dependent endothelial cell binding protein for high molecular weight kininogen (HK) and factor XII; these proteins bind to a site on gC1qR distinct from the C1q-binding site, as C1q did not inhibit HK binding and anti-C1q-blocking mAbs did not block HK binding.","method":"HK-affinity chromatography of HUVEC membrane proteins in presence/absence of ZnCl2, SDS-PAGE, Western blot with anti-gC1qR mAbs, ligand blot, 125I-HK binding inhibition assay","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — affinity chromatography, N-terminal sequencing, multiple binding assays, functional inhibition, single lab","pmids":["8710908"],"is_preprint":false},{"year":2000,"finding":"gC1q-R/p33 is a direct cellular receptor for InlB, the Listeria monocytogenes invasion protein; InlB binds gC1qR directly (shown by affinity chromatography and ELISA), and transfection of non-permissive cells with human gC1qR promotes entry of InlB-coated beads. gC1qR associates with the adaptor Gab1 upon InlB stimulation and mediates InlB-dependent PI3-kinase membrane recruitment and activation.","method":"Affinity chromatography, ELISA, transfection of non-permissive GPC16 cells, entry assay with InlB-coated beads, co-immunoprecipitation (gC1qR with Gab1), antibody/C1q inhibition of entry","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal functional assays (gain-of-function transfection, inhibition with antibody and C1q), direct binding demonstrated, Co-IP for downstream signaling","pmids":["10747014"],"is_preprint":false},{"year":2000,"finding":"HCV core protein binds gC1qR (identified by yeast two-hybrid screen) and inhibits T-cell proliferation via gC1qR; the core binds the region spanning amino acids 188–259 of gC1qR (distinct from C1q-binding site), and anti-gC1qR antibody reverses core-induced T-cell proliferation inhibition.","method":"Yeast two-hybrid screen of human T-cell library, biochemical binding analysis with deletion mutants, T-cell proliferation assay with antibody reversal","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus functional T-cell assay with antibody rescue, binding domain mapped by deletion analysis","pmids":["11086025"],"is_preprint":false},{"year":2000,"finding":"Staphylococcus aureus protein A directly binds platelet gC1qR/p33; the protein A-binding domain on gC1qR lies outside the N-terminal alpha helix (residues 74–95), distinct from the C1q-binding site. gC1qR capture of S. aureus was inhibited by soluble rgC1qR, anti-gC1qR F(ab')2, and rabbit IgG, and tyrosine inactivation of protein A abrogated gC1qR binding.","method":"Affinity capture with fixed S. aureus/protein A-agarose, solid-phase ELISA with biotinylated gC1qR, inhibition studies, truncated gC1qR mutant lacking residues 74–95","journal":"Infection and immunity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple binding assays + domain mapping with truncation mutant, single lab","pmids":["10722602"],"is_preprint":false},{"year":2001,"finding":"Factor XII binds to a multiprotein receptor complex on endothelial cell membranes comprising gC1qR, urokinase plasminogen activator receptor (uPAR), and cytokeratin 1; antibodies to gC1qR, uPAR, and CK1 each block FXII binding. FXII binds via a region in its fibronectin type II domain (peptide YHK9 from residues 39–47).","method":"Flow cytometry binding assays with FITC/biotin-FXII, confocal and electron microscopy co-localization, antibody blocking assays, recombinant receptor inhibition","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (flow cytometry, confocal, EM, soluble receptor competition, domain-mapping peptide), single lab","pmids":["11986212"],"is_preprint":false},{"year":2001,"finding":"Factor XII, prekallikrein, and HK activation (conversion of prekallikrein to kallikrein) is catalyzed by gC1qR and cytokeratin 1 in a zinc-dependent, Factor XII-dependent manner; normal plasma activation on endothelial cells is inhibited by antibodies to gC1qR and cytokeratin 1.","method":"Purified protein contact activation assay, plasma activation assay on endothelial cells, antibody inhibition","journal":"Thrombosis and haemostasis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reconstitution with purified proteins, antibody-inhibition confirmation, single lab","pmids":["11204562"],"is_preprint":false},{"year":1999,"finding":"gC1qR binds the light chain of HK (zinc-dependent) while cytokeratin 1 binds the heavy-chain domain 3 of HK; anti-gC1qR antibody inhibits HK binding to endothelial cells by 72% and combined anti-gC1qR + anti-CK1 inhibits by 86%.","method":"Affinity chromatography of HUVEC membranes with HK or domain 3 peptide columns, zinc-dependent elution, Western blot, antibody inhibition of 125I-HK binding","journal":"Clinical immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity purification with N-terminal sequencing, domain specificity determined, antibody inhibition, single lab","pmids":["10479529"],"is_preprint":false},{"year":1997,"finding":"cC1qR (calreticulin) and gC1qR form a complex; biotinylated cC1qR binds recombinant and native gC1qR with binding sites at N-terminal residues 76–93 and 204–218. Anti-gC1qR mAbs 60.11, 46.23, and 74.5.2 inhibit this interaction, and co-immunoprecipitation of Raji cell membranes with anti-gC1qR mAbs co-precipitates cC1qR.","method":"Solid-phase ELISA with biotinylated cC1qR and recombinant gC1qR, antibody inhibition, co-immunoprecipitation from cell membranes","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ELISA binding + Co-IP from cell membranes + domain mapping, single lab","pmids":["9233640"],"is_preprint":false},{"year":1999,"finding":"gC1qR binds the C-terminal cytoplasmic domain of the alpha1B-adrenergic receptor (residues 344–516, specifically the arginine-rich residues 369–378) as identified by yeast two-hybrid; co-expression of gC1qR with the receptor causes redistribution of the receptor from plasma membrane to intracellular locations and receptor downregulation.","method":"Yeast two-hybrid screen of rat liver cDNA library, co-immunoprecipitation from COS-7 cells, confocal co-localization, deletion mutant mapping","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid, Co-IP, confocal, deletion mutant, single lab","pmids":["10409668"],"is_preprint":false},{"year":2002,"finding":"HABP1/C1QBP is an endogenous substrate for MAP kinase (ERK); in vitro kinase assay demonstrates ERK phosphorylates HABP1, and HABP1 co-immunoprecipitates with activated ERK in cells. Upon PMA stimulation, HABP1 translocates from cytoplasm to nucleus in an ERK-dependent manner (blocked by PD98059).","method":"In vitro kinase assay, co-immunoprecipitation with activated ERK, subcellular fractionation/immunofluorescence after PMA treatment, ERK inhibitor PD98059","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus Co-IP plus pharmacological inhibition confirming pathway, single lab","pmids":["11866440"],"is_preprint":false},{"year":2004,"finding":"Direct binding of HCV core protein to gC1qR on T cells impairs Lck and Akt activation; this binding is inhibitable by anti-gC1qR antibody or soluble gC1qR, is reduced by gC1qR siRNA knockdown, and enhanced by gC1qR transfection. BIAcore analysis gives binding affinity constant of 3.8×10−7 M.","method":"BIAcore surface plasmon resonance, flow cytometry binding, siRNA knockdown of gC1qR, transfection of guinea pig cells with human gC1qR, Western blot for Lck/ZAP-70/Akt phosphorylation","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — SPR affinity measurement + siRNA loss-of-function + gain-of-function transfection + signaling readout, single lab","pmids":["15163734"],"is_preprint":false},{"year":2003,"finding":"HCV core binding to gC1qR on T cells induces G0/G1 cell cycle arrest by stabilizing the CDK inhibitor p27Kip1, thereby preventing CDK2/4 and cyclin E/D expression, pRb phosphorylation, and G1→S transition; arrest is reversible by anti-gC1qR antibody.","method":"T-cell proliferation assay, flow cytometry cell cycle analysis, Western blot for CDK2/4, cyclin E/D, pRb, p27Kip1, antibody rescue experiment","journal":"Virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell cycle assay with antibody rescue + multiple molecular readouts, single lab","pmids":["14517080"],"is_preprint":false},{"year":2005,"finding":"HCV core/gC1qR ligation on T cells induces SOCS1 and SOCS3 expression, which disrupts STAT phosphorylation and inhibits IFN-γ production; siRNA silencing of either SOCS1 or SOCS3 abrogates the inhibitory effect of core on T-cell IFN-γ production.","method":"T-cell functional assay, Western blot for SOCS1/3 and p-STAT, siRNA knockdown of SOCS1 and SOCS3, IFN-γ ELISA","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function confirming SOCS-mediated pathway, functional readout, single lab","pmids":["16306613"],"is_preprint":false},{"year":2009,"finding":"gC1qR inhibits RIG-I- and MDA5-dependent antiviral signaling by translocating to the mitochondrial outer membrane upon dsRNA/virus stimulation and interacting with the adaptor VISA/MAVS/IPS-1/Cardif, thereby disrupting RIG-I/MDA5 signaling and promoting virus replication. Knockdown of gC1qR enhances RIG-I-dependent antiviral signaling.","method":"Co-immunoprecipitation (gC1qR with MAVS), siRNA knockdown, subcellular fractionation showing translocation, viral replication assays","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating interaction with MAVS, siRNA with functional antiviral readout, localization by fractionation, single lab with orthogonal methods","pmids":["19164550"],"is_preprint":false},{"year":2001,"finding":"MT1-MMP cleaves gC1qR proteolytically at Gly79↓Gln80 in vitro and in cell culture; the hemopexin-like domain of MT1-MMP is required for proteolysis. A catalytically inactive MT1-MMP retains gC1qR binding ability and acts as a cell-surface receptor for gC1qR.","method":"In vitro proteolysis assay with recombinant proteins, cell culture experiments, MT1-MMP domain deletion constructs, hydroxamate inhibitor studies, co-precipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro proteolysis with defined cleavage site + domain deletion constructs + cell culture validation, single lab","pmids":["11773076"],"is_preprint":false},{"year":2012,"finding":"p32/gC1qR is required for mitochondrial translation; p32-knockout mice show mid-gestation lethality and severe respiratory chain dysfunction. Recombinant p32 binds mitochondrial mRNA (not DNA), endogenous p32 associates with all mitochondrial mRNA species in vivo, and co-immunoprecipitation shows p32 associates with the mitoribosome.","method":"p32-knockout mouse generation, primary embryonic fibroblast analysis, in vitro RNA-binding assay, co-immunoprecipitation with mitoribosome, mitochondrial respiratory chain assays","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — knockout mouse phenotype + in vitro RNA-binding reconstitution + mitoribosome Co-IP + multiple respiratory chain readouts, single lab with multiple orthogonal methods","pmids":["22904065"],"is_preprint":false},{"year":2007,"finding":"Plasmodium falciparum-infected red blood cells use gC1qR/HABP1/p32 as a receptor to bind to human brain microvascular endothelial cells and to platelets for clumping, as demonstrated by in vitro cytoadherence assays.","method":"In vitro cytoadherence assay on cells expressing gC1qR, blocking with anti-gC1qR antibodies and recombinant gC1qR","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cytoadherence assay with antibody blocking, single lab","pmids":["17907801"],"is_preprint":false},{"year":2011,"finding":"Cell-surface gC1qR is required for growth factor-induced lamellipodia formation and cell migration; gC1qR is concentrated in lamellipodia with CD44, monosialoganglioside, actin, and phospho-FAK, and gC1qR depletion reduces FAK activation, receptor tyrosine kinase activation, lamellipodia formation, cell migration, and in vivo metastasis.","method":"siRNA knockdown, immunofluorescence co-localization in lamellipodia, Western blot for FAK/RTK phosphorylation, migration assay, xenograft mouse model","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with multiple readouts (signaling, migration, in vivo metastasis), single lab","pmids":["21536672"],"is_preprint":false},{"year":2013,"finding":"Soluble gC1qR binds to endothelial cells via residues 174–180, with binding mediated through surface-bound fibrinogen; this binding induces upregulation of bradykinin receptor B1R expression, an effect diminished by gC1qR lacking residues 174–180 and 154–162 and inhibited by anti-fibrinogen antibody.","method":"Solid-phase binding assay, deconvolution fluorescence microscopy, flow cytometry for B1R expression, deletion mutant analysis, antibody inhibition","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain mapping with deletion mutants + functional receptor upregulation assay, single lab","pmids":["24319267"],"is_preprint":false},{"year":2001,"finding":"gC1q-R/GABA(A) receptor beta subunit interaction: gC1qR co-purifies with immunopurified GABA(A) receptors and exhibits reciprocal co-immunoprecipitation from rat brain membranes. Yeast two-hybrid showed all beta subunits (but not alpha1 or gamma2) interact with gC1qR via a 15-amino-acid stretch (residues 399–413) containing 7 positively charged residues.","method":"Immunopurification from bovine brain, mass spectrometric identification, reciprocal Co-IP from rat brain membranes, yeast two-hybrid with deletion mutants","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP from native brain tissue + yeast two-hybrid domain mapping, single lab","pmids":["11350968"],"is_preprint":false},{"year":2017,"finding":"Biallelic loss-of-function mutations in C1QBP cause combined respiratory-chain enzyme deficiency of complexes I, III, and IV; complementation of C1qbp−/− MEFs with wild-type but not mutagenized C1qbp restores OXPHOS protein levels and mitochondrial enzyme activities, establishing C1QBP as essential for mitochondrial energy metabolism.","method":"Patient genetics, C1qbp−/− MEF complementation assay (wild-type vs. mutant), respiratory chain enzyme activity assays, OXPHOS complex protein levels","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — complementation rescue with wild-type vs. mutant in knockout MEFs + biochemical enzyme assays + replicated across multiple unrelated families","pmids":["28942965"],"is_preprint":false},{"year":2017,"finding":"Cardiomyocyte-specific deletion of p32/C1qbp causes contractile dysfunction, cardiac dilatation, fibrosis, decreased COX1 expression, reduced oxygen consumption, and increased oxidative stress. p32-deficient hearts show constitutive AMPK phosphorylation, reduced mTOR signaling, increased FGF21/integrated stress response, and impaired urea cycle, with median lifespan ~14 months.","method":"Cre-loxP cardiac-specific knockout, echocardiography, electron microscopy of mitochondria, Western blot for AMPK/mTOR/signaling proteins, metabolic analysis, Seahorse respirometry","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — tissue-specific knockout with multiple functional, ultrastructural, and metabolic readouts, comprehensive mechanistic characterization","pmids":["28498888"],"is_preprint":false},{"year":2018,"finding":"p32/C1qbp interacts with the E2 component of the pyruvate dehydrogenase (PDH) complex (dihydrolipoamide S-acetyltransferase, DLAT) and positively regulates PDH activity; p32-deficient DCs show impaired LPS-induced citrate increase, and PDH inhibitor reproduces the p32-null phenotype of decreased DC maturation in vivo.","method":"Co-immunoprecipitation of p32 with DLAT, PDH activity assay in p32-deficient DCs, metabolic analysis, PDH inhibitor in vivo study in p32-null mice","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP + enzymatic activity assay + pharmacological phenocopy in vivo, multiple orthogonal methods, single lab","pmids":["30428349"],"is_preprint":false},{"year":2016,"finding":"Subcellular fractionation combined with Co-IP-MS identified DLAT (dihydrolipoyllysine-residue acetyltransferase, E2 subunit of PDH complex) as a novel mitochondrial interacting partner of C1QBP; PDH activity is affected by C1QBP expression level.","method":"Subcellular fractionation coupled with Co-IP and mass spectrometry, validation by Co-IP/Western blot, PDH activity assay","journal":"Analytical and bioanalytical chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP-MS with enzymatic activity validation, single lab","pmids":["26753982"],"is_preprint":false},{"year":2019,"finding":"C1QBP forms a complex (MRC) with MRE11 and RAD50 that stabilizes MRE11/RAD50 but inhibits MRE11 nuclease activity by preventing DNA/chromatin binding. Upon DNA double-strand breaks, ATM phosphorylates MRE11 at S676/S678, dissociating the MRC and allowing MRN complex assembly and recruitment to DSBs; either excess or insufficient C1QBP impairs DSB repair.","method":"Co-immunoprecipitation, MRE11 nuclease activity assay, chromatin fractionation, ATM kinase assay, phosphorylation site mutagenesis, C1QBP knockdown/overexpression with DSB response readouts","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — Co-IP + nuclease activity assay + phospho-mutagenesis + chromatin recruitment assay + multiple genetic perturbations, comprehensive mechanistic study","pmids":["31353207"],"is_preprint":false},{"year":2014,"finding":"C1QBP interacts with YBX1 and negatively regulates YBX1 activation; C1QBP knockdown enhances YBX1 phosphorylation and nuclear translocation in renal cell carcinoma.","method":"Co-immunoprecipitation followed by mass spectrometry, validation by IP/Western blot, siRNA knockdown of C1QBP, nuclear fractionation","journal":"Journal of proteome research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP-MS with functional validation (siRNA + nuclear translocation), single lab","pmids":["25497084"],"is_preprint":false},{"year":2017,"finding":"C1QBP interacts with YBX1 and suppresses YBX1 activation by altering YBX1 phosphorylation and nuclear translocation in RCC cells; this suppresses AR-modulated MMP9 signaling to inhibit cell invasion, confirmed in orthotopic in vivo mouse model.","method":"Co-immunoprecipitation, Western blot for YBX1 phosphorylation and nuclear translocation, siRNA/overexpression functional assays, orthotopic mouse model","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional in vitro and in vivo validation, single lab","pmids":["28107702"],"is_preprint":false},{"year":2015,"finding":"ZNF32 transcriptionally activates C1QBP expression; C1QBP is a direct target gene of ZNF32 that inactivates the p38 MAPK pathway to protect against oxidative stress-induced apoptosis. ZNF32-deficient cells show reduced C1QBP and increased p38 MAPK activation.","method":"Chromatin immunoprecipitation (ZNF32 binding to C1QBP promoter), ZNF32 knockdown/overexpression with C1QBP and p38 MAPK readouts, luciferase promoter assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrating direct transcriptional regulation + functional knockdown assays, single lab","pmids":["26497555"],"is_preprint":false},{"year":2020,"finding":"The FXII fibronectin type II (FnII) domain binds gC1qR in a Zn2+-dependent, asymmetric fashion on the gC1qR trimer; crystal structure of the FXIIFnII–gC1qR complex reveals Arg36 and Arg65 of FXII contact two distinct negatively charged pockets of gC1qR. gC1qR residues Asp185 and His187 coordinate Zn2+ adjacent to the FXII-binding site; binding induces allosteric ordering of the anionic G1-loop. HK domain 5 (HKD5) binds only one high-affinity site per gC1qR trimer via a central G3-loop (steric occlusion mechanism). gC1qR clusters FXII and HK into a ~500 kDa ternary complex and stimulates coagulation in a FXII-dependent manner.","method":"Crystal structure determination, SPR with mutagenesis, gel filtration for ternary complex, plasma-based FXII-dependent coagulation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis validated by SPR plus functional plasma coagulation assay, comprehensive multi-method study","pmids":["32559765"],"is_preprint":false},{"year":2021,"finding":"C1qbp is intrinsically required for effector CD8+ T cell differentiation; C1qbp-deficient CD8+ T cells fail to increase mitochondrial respiratory capacity upon activation, resulting in diminished acetyl-CoA and elevated fumarate and 2-hydroxyglutarate, leading to H3K27 hypoacetylation and hypermethylation and transcriptional silencing of effector genes. Fumarate supplementation or HDAC inhibitor + acetate reversed the differentiation defect.","method":"Conditional C1qbp knockout in CD8+ T cells, metabolomics, histone modification analysis (ChIP), Seahorse respirometry, viral infection models, pharmacological rescue","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with metabolomics + epigenetic analysis + pharmacological rescue, comprehensive mechanistic characterization, single lab","pmids":["34860557"],"is_preprint":false},{"year":2020,"finding":"Active caspase-1 cleaves gC1qR at two caspase-1 cleavage sites, preventing mitochondrial import of gC1qR; this results in aerobic glycolysis (Warburg effect) and enhanced cell proliferation. Non-mitochondrial gC1qR localization correlated with caspase-1 activation and tumor grade in colorectal carcinoma patients.","method":"Caspase-1 cleavage assay in vitro, mitochondrial import assay, metabolic profiling of glycolysis/OXPHOS, cell proliferation assay, immunohistochemistry correlation in patient tumors","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro cleavage assay + mitochondrial import assay + metabolic readout, single lab","pmids":["33102234"],"is_preprint":false},{"year":1999,"finding":"gC1qR binds directly to the D domain of fibrinogen/fibrin (specifically the C-terminal segment of the fibrinogen gamma chain in fragment D-100, lost upon further plasmin digestion to D-60) and inhibits fibrin polymerization in a dose-dependent manner; at 2:1 molar ratio (gC1qR:fibrinogen), fibrin clot formation is completely inhibited.","method":"Solid-phase ELISA with biotinylated gC1qR, fibrin polymerization turbidity assay, binding to fibrinogen degradation fragments","journal":"Clinical immunology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — reconstitution binding assay + functional fibrin polymerization inhibition + domain mapping, single lab","pmids":["10075865"],"is_preprint":false},{"year":1998,"finding":"Soluble recombinant gC1qR (rgC1qR) enhances blood coagulation: it dose-dependently shortens prothrombin time and plasma recalcification time, with procoagulant activity measurable in factor XII- or factor XI-deficient plasma, suggesting activity not exclusively through the contact system.","method":"Prothrombin time assay in human plasma, plasma recalcification time assay, factor-deficient plasma studies, chromogenic substrate assays for thrombin and factor Xa","journal":"Blood coagulation & fibrinolysis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional plasma coagulation assays with recombinant protein, multiple coagulation pathway dissection, single lab","pmids":["9607116"],"is_preprint":false},{"year":2021,"finding":"Exosomal CD44v6/C1QBP complex from pancreatic cancer cells is delivered to the plasma membrane of hepatic stellate cells (HSCs), leading to phosphorylation of IGF-1 signaling molecules, HSC activation, and liver fibrosis promoting metastasis. C1QBP knockdown suppresses this effect in vitro and in vivo.","method":"Exosome isolation, stable lentiviral knockdown/overexpression, mouse liver metastasis models, Western blot for IGF-1R phosphorylation, HSC activation markers","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockdown/overexpression in multiple in vivo models + signaling readouts, single lab","pmids":["33827783"],"is_preprint":false},{"year":2017,"finding":"C1QBP in lipid rafts is required for IGF-1-induced hepatic metastasis of pancreatic cancer; IGF-1 triggers translocation of C1QBP from cytoplasm to lipid rafts and formation of a CD44v6/C1QBP complex, which promotes IGF-1R phosphorylation and downstream PI3K/MAPK signaling. C1QBP knockdown suppresses hepatic metastasis in nude mice.","method":"Lipid raft fractionation, Co-IP of CD44v6 and C1QBP, Western blot for IGF-1R/PI3K/MAPK phosphorylation, siRNA knockdown, hepatic metastasis mouse model","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lipid raft fractionation + Co-IP + in vivo knockdown model, single lab","pmids":["28608366"],"is_preprint":false},{"year":2002,"finding":"HABP1/gC1qR forms a noncovalently associated homotrimer in equilibrium with a covalently linked hexamer (dimer of trimers) through disulfide bonds at Cys186; the hexameric form shows enhanced affinity for hyaluronan, gC1q, and mannosylated BSA compared with the trimer.","method":"Size-exclusion chromatography, glutaraldehyde cross-linking, fluorescence spectroscopy with Hg2+, Cys186 chemical modification, ligand-binding assays comparing trimer vs. hexamer","journal":"European journal of biochemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical characterization with mutagenesis (Cys186 modification) and multiple ligand-binding comparisons, single lab","pmids":["11784324"],"is_preprint":false},{"year":2012,"finding":"DC-SIGN, C1q, and gC1qR form a trimolecular receptor complex on immature dendritic cells; DC-SIGN binds directly to C1q (and its globular domain) in a Ca2+-dependent manner at its mannose-binding pocket, and C1q/gC1qR associate with DC-SIGN on blood DC precursors and immature DCs by immunofluorescence and antigen-capture ELISA.","method":"ELISA, flow cytometry, immunoprecipitation, surface plasmon resonance, immunofluorescence microscopy, mannan competition, calcium chelation","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — SPR + Co-IP + ELISA + imaging, multiple orthogonal methods, single lab","pmids":["22700724"],"is_preprint":false},{"year":2022,"finding":"C1QBP directly interacts with the C9-ALS-associated proline-arginine dipeptide repeat protein (PR50); C1QBP knockdown in HMC3 microglial cells induces NLRP3 inflammasome activation similar to PR50 expression. The compound syringin blocks the PR50-C1QBP interaction and reduces PR50-induced NLRP3 inflammasome activation.","method":"Co-immunoprecipitation, siRNA knockdown of C1QBP, NLRP3 inflammasome activity assay, syringin treatment/competitive inhibition","journal":"Cells","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP + siRNA knockdown, single lab, limited mechanistic depth","pmids":["36231090"],"is_preprint":false},{"year":2005,"finding":"HABP1/gC1qR localizes to the Golgi apparatus and disperses throughout the cell during mitosis, resembling the distribution dynamics of its ligand hyaluronan.","method":"Indirect immunofluorescence with Golgi and mitochondrial markers across cell cycle stages","journal":"Cell research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — immunofluorescence localization without functional consequence demonstrated, single lab","pmids":["15780180"],"is_preprint":false},{"year":2016,"finding":"Mutational analysis of C1q globular head modules revealed that Arg162 of the ghA module is central to C1q-gC1qR interaction, while an Arg114Glu substitution in ghB enhanced binding; ghA, ghB, and ghC each independently bind gC1qR and attenuate PHA-stimulated PBMC proliferation.","method":"Recombinant globular head module expression, substitution mutagenesis, ELISA binding assays, cell proliferation assay","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — site-directed mutagenesis + binding assays + functional proliferation assay, single lab","pmids":["28018340"],"is_preprint":false}],"current_model":"C1QBP (p32/gC1qR/HABP1) is a homotrimeric, multifunctional protein that resides primarily in the mitochondrial matrix—where it binds mitochondrial mRNAs, associates with the mitoribosome, and interacts with the PDH complex E2 subunit (DLAT) to support mitochondrial translation and oxidative phosphorylation—but also traffics to other compartments where it serves as a multiligand docking platform: on cell surfaces it binds C1q, HK, FXII (zinc-dependently, via a defined crystal structure), vitronectin, fibrinogen, InlB, HCV core, S. aureus protein A, and numerous other ligands to modulate complement, kinin, coagulation, and antiviral (MAVS/RIG-I) signaling; it also forms a nuclear complex with MRE11/RAD50 that is dissociated by ATM-mediated phosphorylation to control homologous recombination, interacts with YBX1 to suppress oncoprotein signaling, acts as a substrate for ERK (translocating to the nucleus upon mitogenic stimulation), and can be cleaved by caspase-1 to prevent mitochondrial import and redirect metabolism toward aerobic glycolysis."},"narrative":{"mechanistic_narrative":"C1QBP (p32/gC1qR/HABP1) is a homotrimeric multifunctional protein whose primary residence is the mitochondrial matrix, where it supports mitochondrial gene expression and energy metabolism, but which also operates as a multiligand docking platform across the cell surface, cytoplasm, and nucleus [PMID:9531316, PMID:22904065, PMID:32559765]. An N-terminal presequence directs import into the mitochondrial matrix, where the mature protein binds mitochondrial mRNAs and associates with the mitoribosome to drive mitochondrial translation; loss of C1QBP causes mid-gestation lethality and severe respiratory-chain dysfunction in mice, and biallelic loss-of-function mutations in humans cause combined deficiency of OXPHOS complexes I, III, and IV [PMID:9531316, PMID:22904065, PMID:28942965]. Within the matrix it binds the PDH E2 subunit DLAT and positively regulates pyruvate dehydrogenase activity, linking it to acetyl-CoA supply, and tissue-specific deletion produces cardiac contractile failure with AMPK activation and integrated stress responses while CD8+ T-cell-specific loss impairs effector differentiation through metabolite-driven histone hypoacetylation and hypermethylation [PMID:30428349, PMID:26753982, PMID:28498888, PMID:34860557]. The protein assembles as a trimer in equilibrium with a disulfide-linked hexamer, and a crystal structure of the FXII fibronectin type II domain bound to the gC1qR trimer defines the zinc-dependent, asymmetric binding chemistry by which it clusters FXII and high-molecular-weight kininogen into a procoagulant ternary complex on endothelial cells together with uPAR and cytokeratin 1 [PMID:11784324, PMID:32559765, PMID:11986212, PMID:8710908]. Through spatially distinct binding sites it engages an extensive ligand repertoire — C1q, vitronectin, fibrinogen, and microbial proteins including Listeria InlB, HCV core, and S. aureus protein A — to modulate complement, kinin, coagulation, and host-pathogen interactions [PMID:8900153, PMID:8710908, PMID:10747014, PMID:11086025, PMID:10722602, PMID:10075865, PMID:28018340]. C1QBP additionally restrains innate antiviral signaling by translocating to the mitochondrial outer membrane and binding MAVS to suppress RIG-I/MDA5 responses, forms a nuclear complex with MRE11/RAD50 (the MRC) that is dissociated by ATM-mediated MRE11 phosphorylation to license homologous-recombination repair, and acts as an ERK substrate that relocates to the nucleus upon mitogenic stimulation [PMID:19164550, PMID:31353207, PMID:11866440]. In cancer it interacts with YBX1 to suppress oncogenic invasion signaling, and caspase-1 cleavage prevents its mitochondrial import to redirect metabolism toward aerobic glycolysis [PMID:25497084, PMID:28107702, PMID:33102234].","teleology":[{"year":1996,"claim":"Established that gC1qR is a cell-surface receptor whose ligand-binding repertoire extends beyond C1q, defining anatomically distinct binding sites for vitronectin and for the contact-system proteins HK and factor XII.","evidence":"Affinity chromatography of endothelial membranes and recombinant protein binding assays with truncation/inhibition mapping","pmids":["8900153","8710908"],"confidence":"High","gaps":["Structural basis of distinct ligand sites not resolved","Physiological relevance of cell-surface display from a mitochondrial protein not addressed"]},{"year":1997,"claim":"Demonstrated that gC1qR physically associates with calreticulin (cC1qR), an early hint that it acts as a scaffold forming multiprotein receptor complexes rather than a lone receptor.","evidence":"Solid-phase ELISA, domain mapping, and Co-IP from cell membranes","pmids":["9233640"],"confidence":"Medium","gaps":["Functional consequence of the cC1qR/gC1qR complex unclear","Single lab"]},{"year":1998,"claim":"Defined the dual localization paradox by identifying an N-terminal mitochondrial targeting presequence directing the protein to the matrix, while also showing soluble recombinant protein has procoagulant activity in plasma.","evidence":"GFP-presequence fusion, mitoplast fractionation, and plasma coagulation assays","pmids":["9531316","9607116"],"confidence":"High","gaps":["Mechanism by which a matrix protein reaches the cell surface unexplained","Molecular basis of procoagulant activity not defined"]},{"year":1999,"claim":"Extended the coagulation/kinin role by mapping gC1qR binding to the HK light chain and to the fibrinogen D domain, where it inhibits fibrin polymerization, positioning the protein at multiple nodes of the contact and clotting systems.","evidence":"Affinity chromatography with domain peptides, fibrin turbidity assays, and antibody inhibition","pmids":["10479529","10075865"],"confidence":"Medium","gaps":["In vivo relevance of fibrin inhibition versus procoagulant activity unreconciled","Single lab"]},{"year":2000,"claim":"Revealed gC1qR as a hijacked microbial receptor, serving as the direct entry receptor for Listeria InlB (recruiting Gab1/PI3K), binding HCV core to suppress T cells, and binding S. aureus protein A.","evidence":"Yeast two-hybrid, affinity chromatography, gain-of-function transfection entry assays, and Co-IP","pmids":["10747014","11086025","10722602"],"confidence":"High","gaps":["How surface gC1qR transduces signals lacking a transmembrane domain unresolved","Receptor partners required for signaling incompletely defined"]},{"year":2001,"claim":"Defined the endothelial contact-system receptor complex (gC1qR/uPAR/cytokeratin 1) that binds and activates factor XII/prekallikrein zinc-dependently, and identified gC1qR as an ERK substrate that translocates to the nucleus, linking it to mitogenic signaling and to GABA(A) receptor beta subunits in brain.","evidence":"Flow cytometry/EM co-localization, purified-protein activation assays, in vitro kinase assay with PD98059, and reciprocal Co-IP from brain","pmids":["11986212","11204562","11866440","11350968"],"confidence":"High","gaps":["Functional role of nuclear translocation not defined","GABA(A) interaction physiology unexplored"]},{"year":2002,"claim":"Characterized the quaternary structure, showing the protein equilibrates between a noncovalent trimer and a disulfide-linked hexamer (via Cys186) with the hexamer exhibiting enhanced ligand affinity.","evidence":"Size-exclusion chromatography, cross-linking, Cys186 modification, and comparative ligand binding","pmids":["11784324"],"confidence":"Medium","gaps":["In vivo prevalence of hexamer not established","Single lab"]},{"year":2009,"claim":"Identified an immunoregulatory mechanism whereby gC1qR translocates to the mitochondrial outer membrane and binds MAVS to dampen RIG-I/MDA5 antiviral signaling, promoting viral replication.","evidence":"Co-IP with MAVS, siRNA knockdown with antiviral readouts, and fractionation showing translocation","pmids":["19164550"],"confidence":"High","gaps":["Stimulus-driven trafficking mechanism to outer membrane unresolved","Single lab"]},{"year":2012,"claim":"Established the core mitochondrial function: C1QBP binds mitochondrial mRNAs and the mitoribosome and is essential for mitochondrial translation, with knockout causing embryonic lethality and respiratory-chain failure.","evidence":"p32-knockout mouse, in vitro RNA-binding assays, and mitoribosome Co-IP","pmids":["22904065"],"confidence":"High","gaps":["Specificity/mechanism of mRNA binding not structurally defined","Role at the mitoribosome step not resolved"]},{"year":2017,"claim":"Cemented C1QBP as essential for human and tissue energy metabolism through disease genetics, complementation rescue, and a cardiomyocyte knockout linking its loss to OXPHOS failure, AMPK activation, and integrated stress responses.","evidence":"Patient genetics with C1qbp-/- MEF complementation (WT vs mutant), enzyme assays, and Cre-loxP cardiac knockout with respirometry","pmids":["28942965","28498888"],"confidence":"High","gaps":["Genotype-phenotype spectrum of human mutations incompletely mapped","Tissue-specific vulnerability determinants unclear"]},{"year":2016,"claim":"Connected C1QBP directly to central carbon metabolism by identifying the PDH E2 subunit DLAT as a mitochondrial partner and showing C1QBP positively regulates PDH activity.","evidence":"Subcellular fractionation Co-IP-MS with PDH activity validation, later extended with dendritic-cell knockout and PDH-inhibitor phenocopy","pmids":["26753982","30428349"],"confidence":"High","gaps":["Whether C1QBP regulates PDH directly or via translation of components unresolved","Stoichiometry of DLAT interaction undefined"]},{"year":2019,"claim":"Defined a nuclear genome-stability role: C1QBP forms the MRC complex with MRE11/RAD50 that holds MRE11 nuclease inactive until ATM phosphorylates MRE11 to dissociate the complex and license MRN-mediated DSB repair.","evidence":"Co-IP, nuclease activity assays, ATM kinase assay, phospho-site mutagenesis, and chromatin recruitment with genetic perturbation","pmids":["31353207"],"confidence":"High","gaps":["How nuclear C1QBP pool is established relative to mitochondrial pool unclear","Dosage-sensitivity mechanism not fully defined"]},{"year":2021,"claim":"Demonstrated that C1QBP-dependent mitochondrial metabolism drives epigenetic programming of immune cell fate, with CD8+ T-cell loss causing metabolite imbalances that silence effector genes via histone modification changes.","evidence":"Conditional knockout with metabolomics, ChIP histone-modification analysis, respirometry, and pharmacological rescue","pmids":["34860557"],"confidence":"High","gaps":["Generality across other immune lineages unestablished","Direct chromatin targets of the metabolite shift not enumerated"]},{"year":2020,"claim":"Provided the structural mechanism for contact-system clustering, showing zinc-dependent asymmetric binding of FXII and HK on the gC1qR trimer to form a procoagulant ~500 kDa ternary complex.","evidence":"Crystal structure of FXIIFnII-gC1qR, SPR with mutagenesis, gel filtration, and plasma coagulation assay","pmids":["32559765"],"confidence":"High","gaps":["Structural basis of other ligand interactions still lacking","Physiological control of surface clustering in vivo unresolved"]},{"year":null,"claim":"How C1QBP partitions between mitochondrial, surface, cytoplasmic, and nuclear pools — and what governs the trafficking decisions that switch it between metabolic, signaling, repair, and receptor functions — remains the central unresolved question.","evidence":"No single study reconciles the compartment-switching mechanism","pmids":[],"confidence":"Medium","gaps":["No unifying model for trafficking of a presequence-bearing matrix protein to the cell surface","Regulatory logic selecting among its functions per compartment unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003723","term_label":"RNA binding","supporting_discovery_ids":[17]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,6,30,38]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[24,26,33]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[3,4,18]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0,17,22,23]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,6,19,36]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[11,26]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[11,27]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[17,22,24,31]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[6,30,33,34]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,31,41]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[26]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[17]}],"complexes":["MRE11/RAD50 (MRC)","gC1qR/uPAR/cytokeratin 1 contact-system receptor","mitoribosome","DC-SIGN/C1q/gC1qR"],"partners":["DLAT","MRE11","RAD50","MAVS","YBX1","C1Q","F12","CD44"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q07021","full_name":"Complement component 1 Q subcomponent-binding protein, mitochondrial","aliases":["ASF/SF2-associated protein p32","Glycoprotein gC1qBP","C1qBP","Hyaluronan-binding protein 1","Mitochondrial matrix protein p32","gC1q-R protein","p33","SF2AP32"],"length_aa":282,"mass_kda":31.4,"function":"Multifunctional and multicompartmental protein involved in inflammation and infection processes, ribosome biogenesis, protein synthesis in mitochondria, regulation of apoptosis, transcriptional regulation and pre-mRNA splicing (PubMed:10022843, PubMed:10479529, PubMed:10722602, PubMed:11086025, PubMed:11859136, PubMed:15243141, PubMed:16140380, PubMed:16177118, PubMed:17881511, PubMed:18676636, PubMed:19004836, PubMed:19164550, PubMed:20810993, PubMed:21536856, PubMed:21544310, PubMed:22700724, PubMed:28942965, PubMed:8662673, PubMed:8710908, PubMed:9461517). At the cell surface is thought to act as an endothelial receptor for plasma proteins of the complement and kallikrein-kinin cascades (PubMed:10479529, PubMed:11859136, PubMed:8662673, PubMed:8710908). Putative receptor for C1q; specifically binds to the globular 'heads' of C1q thus inhibiting C1; may perform the receptor function through a complex with C1qR/CD93 (PubMed:20810993, PubMed:8195709). In complex with cytokeratin-1/KRT1 is a high affinity receptor for kininogen-1/HMWK (PubMed:21544310). Can also bind other plasma proteins, such as coagulation factor XII leading to its autoactivation. May function to bind initially fluid kininogen-1 to the cell membrane. The secreted form may enhance both extrinsic and intrinsic coagulation pathways. It is postulated that the cell surface form requires docking with transmembrane proteins for downstream signaling which might be specific for a cell-type or response. By acting as C1q receptor is involved in chemotaxis of immature dendritic cells and neutrophils and is proposed to signal through CD209/DC-SIGN on immature dendritic cells, through integrin alpha-4/beta-1 during trophoblast invasion of the decidua, and through integrin beta-1 during endothelial cell adhesion and spreading (PubMed:16140380, PubMed:22700724, PubMed:9461517). Signaling involved in inhibition of innate immune response is implicating the PI3K-AKT/PKB pathway (PubMed:16177118). Required for protein synthesis in mitochondria (PubMed:28942965). In mitochondrial translation may be involved in formation of functional 55S mitoribosomes; the function seems to involve its RNA-binding activity (By similarity). Acts as a RNA modification reader, which specifically recognizes and binds mitochondrial RNAs modified by C5-methylcytosine (m5C) in response to stress, and promotes recruitment of the mitochondrial degradosome complex, leading to their degradation (PubMed:39019044). May be involved in the nucleolar ribosome maturation process; the function may involve the exchange of FBL for RRP1 in the association with pre-ribosome particles (By similarity). Involved in regulation of RNA splicing by inhibiting the RNA-binding capacity of SRSF1 and its phosphorylation (PubMed:10022843, PubMed:21536856). Is required for the nuclear translocation of splicing factor U2AF1L4 (By similarity). Involved in regulation of CDKN2A- and HRK-mediated apoptosis. Stabilizes mitochondrial CDKN2A isoform smARF (PubMed:17486078). May be involved in regulation of FOXC1 transcriptional activity and NFY/CCAAT-binding factor complex-mediated transcription (PubMed:15243141, PubMed:18676636). May play a role in antibacterial defense as it can bind to cell surface hyaluronan and inhibit Streptococcus pneumoniae hyaluronate lyase (PubMed:19004836). May be involved in modulation of the immune response; ligation by HCV core protein is resulting in suppression of interleukin-12 production in monocyte-derived dendritic cells (PubMed:11086025, PubMed:17881511). Involved in regulation of antiviral response by inhibiting RIGI- and IFIH1-mediated signaling pathways probably involving its association with MAVS after viral infection (PubMed:19164550). Acts as a regulator of DNA repair via homologous recombination by inhibiting the activity of MRE11: interacts with unphosphorylated MRE11 and RAD50 in absence of DNA damage, preventing formation and activity of the MRN complex. Following DNA damage, dissociates from phosphorylated MRE11, allowing formation of the MRN complex (PubMed:31353207) (Microbial infection) Involved in HIV-1 replication, presumably by contributing to splicing of viral RNA (Microbial infection) In infection processes acts as an attachment site for microbial proteins, including Listeria monocytogenes internalin B (InlB) and Staphylococcus aureus protein A (Microbial infection) Involved in replication of Rubella virus","subcellular_location":"Mitochondrion matrix; Nucleus; Nucleus, nucleolus; Cell membrane; Secreted; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q07021/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/C1QBP","classification":"Not Classified","n_dependent_lines":493,"n_total_lines":1208,"dependency_fraction":0.40811258278145696},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DDX21","stoichiometry":10.0},{"gene":"MYH9","stoichiometry":4.0},{"gene":"ASS1","stoichiometry":0.2},{"gene":"CAPZB","stoichiometry":0.2},{"gene":"DDX6","stoichiometry":0.2},{"gene":"GSTP1","stoichiometry":0.2},{"gene":"HEATR3","stoichiometry":0.2},{"gene":"IGF2BP3","stoichiometry":0.2},{"gene":"LBR","stoichiometry":0.2},{"gene":"LSM14A","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/C1QBP","total_profiled":1310},"omim":[{"mim_id":"620759","title":"POLG ALTERNATIVE READING FRAME; POLGARF","url":"https://www.omim.org/entry/620759"},{"mim_id":"617713","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 33; COXPD33","url":"https://www.omim.org/entry/617713"},{"mim_id":"616895","title":"SURVIVAL-ASSOCIATED MITOCHONDRIAL MELANOMA-SPECIFIC ONCOGENIC NONCODING RNA; SAMMSON","url":"https://www.omim.org/entry/616895"},{"mim_id":"609060","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 1; COXPD1","url":"https://www.omim.org/entry/609060"},{"mim_id":"606652","title":"HEPATITIS A VIRUS CELLULAR RECEPTOR 2; HAVCR2","url":"https://www.omim.org/entry/606652"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/C1QBP"},"hgnc":{"alias_symbol":["gC1Q-R","gC1qR","p32","SF2p32"],"prev_symbol":["HABP1"]},"alphafold":{"accession":"Q07021","domains":[{"cath_id":"3.10.280.10","chopping":"73-138_161-282","consensus_level":"medium","plddt":91.3851,"start":73,"end":282}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q07021","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q07021-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q07021-F1-predicted_aligned_error_v6.png","plddt_mean":75.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=C1QBP","jax_strain_url":"https://www.jax.org/strain/search?query=C1QBP"},"sequence":{"accession":"Q07021","fasta_url":"https://rest.uniprot.org/uniprotkb/Q07021.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q07021/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q07021"}},"corpus_meta":[{"pmid":"18757437","id":"PMC_18757437","title":"Mitochondrial/cell-surface protein p32/gC1qR as a molecular target in tumor cells and tumor stroma.","date":"2008","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/18757437","citation_count":278,"is_preprint":false},{"pmid":"11086025","id":"PMC_11086025","title":"Interaction between complement receptor gC1qR and hepatitis C virus core protein inhibits T-lymphocyte proliferation.","date":"2000","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/11086025","citation_count":257,"is_preprint":false},{"pmid":"10747014","id":"PMC_10747014","title":"gC1q-R/p32, a C1q-binding protein, is a receptor for the InlB invasion protein of Listeria monocytogenes.","date":"2000","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/10747014","citation_count":230,"is_preprint":false},{"pmid":"8710908","id":"PMC_8710908","title":"Identification of the zinc-dependent endothelial cell binding protein for high molecular weight kininogen and factor XII: identity with the receptor that binds to the globular \"heads\" of C1q (gC1q-R).","date":"1996","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8710908","citation_count":202,"is_preprint":false},{"pmid":"33827783","id":"PMC_33827783","title":"Exosome-delivered CD44v6/C1QBP complex drives pancreatic cancer liver metastasis by promoting fibrotic liver microenvironment.","date":"2021","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/33827783","citation_count":165,"is_preprint":false},{"pmid":"11414365","id":"PMC_11414365","title":"gC1q-R/p33, a member of a new class of multifunctional and multicompartmental cellular proteins, is involved in inflammation and infection.","date":"2001","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/11414365","citation_count":151,"is_preprint":false},{"pmid":"9531316","id":"PMC_9531316","title":"The multiligand-binding protein gC1qR, putative C1q receptor, is a mitochondrial protein.","date":"1998","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/9531316","citation_count":147,"is_preprint":false},{"pmid":"11986212","id":"PMC_11986212","title":"Factor XII interacts with the multiprotein assembly of urokinase plasminogen activator receptor, gC1qR, and cytokeratin 1 on endothelial cell membranes.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11986212","citation_count":145,"is_preprint":false},{"pmid":"10722602","id":"PMC_10722602","title":"Staphylococcus aureus protein A recognizes platelet gC1qR/p33: a novel mechanism for staphylococcal interactions with platelets.","date":"2000","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/10722602","citation_count":142,"is_preprint":false},{"pmid":"22904065","id":"PMC_22904065","title":"p32/gC1qR is indispensable for fetal development and mitochondrial translation: importance of its RNA-binding 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one","url":"https://pubmed.ncbi.nlm.nih.gov/24205125","citation_count":19,"is_preprint":false},{"pmid":"28565870","id":"PMC_28565870","title":"C1QBP is upregulated in colon cancer and binds to apolipoprotein A-I.","date":"2017","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28565870","citation_count":19,"is_preprint":false},{"pmid":"28018340","id":"PMC_28018340","title":"Analysis of the Interaction between Globular Head Modules of Human C1q and Its Candidate Receptor gC1qR.","date":"2016","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28018340","citation_count":19,"is_preprint":false},{"pmid":"26973884","id":"PMC_26973884","title":"Soluble gC1qR in Blood and Body Fluids: Examination in a Pancreatic Cancer Patient Cohort.","date":"2015","source":"International journal of cancer research and molecular mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/26973884","citation_count":19,"is_preprint":false},{"pmid":"12506357","id":"PMC_12506357","title":"Sperm surface hyaluronan binding protein (HABP1) interacts with zona pellucida of water buffalo (Bubalus bubalis) through its clustered mannose residues.","date":"2003","source":"Molecular reproduction and development","url":"https://pubmed.ncbi.nlm.nih.gov/12506357","citation_count":18,"is_preprint":false},{"pmid":"17892212","id":"PMC_17892212","title":"The exosporium of B. cereus contains a binding site for gC1qR/p33: implication in spore attachment and/or entry.","date":"2007","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/17892212","citation_count":18,"is_preprint":false},{"pmid":"9607116","id":"PMC_9607116","title":"The soluble recombinant form of a binding protein/receptor for the globular domain of C1q (gC1qR) enhances blood coagulation.","date":"1998","source":"Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis","url":"https://pubmed.ncbi.nlm.nih.gov/9607116","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53133,"output_tokens":10852,"usd":0.161089,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":21416,"output_tokens":5181,"usd":0.118303,"stage2_stop_reason":"end_turn"},"total_usd":0.279392,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"p32/gC1qR contains a 33-amino acid N-terminal presequence that functions as a mitochondrial targeting sequence; a fusion protein of this presequence with GFP translocated to mitochondria of transfected COS-7 cells with proteolytic removal of ~6 kDa, and the mature protein resides in the mitochondrial matrix and/or inner membrane.\",\n      \"method\": \"Confocal laser-scanning microscopy, GFP fusion protein transfection, mitoplast fractionation, immunocytochemistry\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct localization by GFP reporter + colocalization with mitochondrial marker + fractionation, replicated across multiple cell types\",\n      \"pmids\": [\"9531316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Recombinant gC1qR binds the heparin-binding multimeric form of vitronectin (but not the plasma form) with saturable, high-affinity interaction (KD ~20 nM) inhibitable by glycosaminoglycans; this binding site is distinct from the C1q-binding site, as a truncated gC1qR lacking the N-terminal 22 amino acids lost vitronectin binding but retained C1q binding.\",\n      \"method\": \"Recombinant protein expression, affinity chromatography with plasma/serum, solid-phase binding assay, inhibition studies with truncation mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with recombinant proteins, mutagenesis (truncation), KD measured, single lab\",\n      \"pmids\": [\"8900153\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"gC1qR is a zinc-dependent endothelial cell binding protein for high molecular weight kininogen (HK) and factor XII; these proteins bind to a site on gC1qR distinct from the C1q-binding site, as C1q did not inhibit HK binding and anti-C1q-blocking mAbs did not block HK binding.\",\n      \"method\": \"HK-affinity chromatography of HUVEC membrane proteins in presence/absence of ZnCl2, SDS-PAGE, Western blot with anti-gC1qR mAbs, ligand blot, 125I-HK binding inhibition assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — affinity chromatography, N-terminal sequencing, multiple binding assays, functional inhibition, single lab\",\n      \"pmids\": [\"8710908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"gC1q-R/p33 is a direct cellular receptor for InlB, the Listeria monocytogenes invasion protein; InlB binds gC1qR directly (shown by affinity chromatography and ELISA), and transfection of non-permissive cells with human gC1qR promotes entry of InlB-coated beads. gC1qR associates with the adaptor Gab1 upon InlB stimulation and mediates InlB-dependent PI3-kinase membrane recruitment and activation.\",\n      \"method\": \"Affinity chromatography, ELISA, transfection of non-permissive GPC16 cells, entry assay with InlB-coated beads, co-immunoprecipitation (gC1qR with Gab1), antibody/C1q inhibition of entry\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal functional assays (gain-of-function transfection, inhibition with antibody and C1q), direct binding demonstrated, Co-IP for downstream signaling\",\n      \"pmids\": [\"10747014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"HCV core protein binds gC1qR (identified by yeast two-hybrid screen) and inhibits T-cell proliferation via gC1qR; the core binds the region spanning amino acids 188–259 of gC1qR (distinct from C1q-binding site), and anti-gC1qR antibody reverses core-induced T-cell proliferation inhibition.\",\n      \"method\": \"Yeast two-hybrid screen of human T-cell library, biochemical binding analysis with deletion mutants, T-cell proliferation assay with antibody reversal\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus functional T-cell assay with antibody rescue, binding domain mapped by deletion analysis\",\n      \"pmids\": [\"11086025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Staphylococcus aureus protein A directly binds platelet gC1qR/p33; the protein A-binding domain on gC1qR lies outside the N-terminal alpha helix (residues 74–95), distinct from the C1q-binding site. gC1qR capture of S. aureus was inhibited by soluble rgC1qR, anti-gC1qR F(ab')2, and rabbit IgG, and tyrosine inactivation of protein A abrogated gC1qR binding.\",\n      \"method\": \"Affinity capture with fixed S. aureus/protein A-agarose, solid-phase ELISA with biotinylated gC1qR, inhibition studies, truncated gC1qR mutant lacking residues 74–95\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple binding assays + domain mapping with truncation mutant, single lab\",\n      \"pmids\": [\"10722602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Factor XII binds to a multiprotein receptor complex on endothelial cell membranes comprising gC1qR, urokinase plasminogen activator receptor (uPAR), and cytokeratin 1; antibodies to gC1qR, uPAR, and CK1 each block FXII binding. FXII binds via a region in its fibronectin type II domain (peptide YHK9 from residues 39–47).\",\n      \"method\": \"Flow cytometry binding assays with FITC/biotin-FXII, confocal and electron microscopy co-localization, antibody blocking assays, recombinant receptor inhibition\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (flow cytometry, confocal, EM, soluble receptor competition, domain-mapping peptide), single lab\",\n      \"pmids\": [\"11986212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Factor XII, prekallikrein, and HK activation (conversion of prekallikrein to kallikrein) is catalyzed by gC1qR and cytokeratin 1 in a zinc-dependent, Factor XII-dependent manner; normal plasma activation on endothelial cells is inhibited by antibodies to gC1qR and cytokeratin 1.\",\n      \"method\": \"Purified protein contact activation assay, plasma activation assay on endothelial cells, antibody inhibition\",\n      \"journal\": \"Thrombosis and haemostasis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reconstitution with purified proteins, antibody-inhibition confirmation, single lab\",\n      \"pmids\": [\"11204562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"gC1qR binds the light chain of HK (zinc-dependent) while cytokeratin 1 binds the heavy-chain domain 3 of HK; anti-gC1qR antibody inhibits HK binding to endothelial cells by 72% and combined anti-gC1qR + anti-CK1 inhibits by 86%.\",\n      \"method\": \"Affinity chromatography of HUVEC membranes with HK or domain 3 peptide columns, zinc-dependent elution, Western blot, antibody inhibition of 125I-HK binding\",\n      \"journal\": \"Clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity purification with N-terminal sequencing, domain specificity determined, antibody inhibition, single lab\",\n      \"pmids\": [\"10479529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"cC1qR (calreticulin) and gC1qR form a complex; biotinylated cC1qR binds recombinant and native gC1qR with binding sites at N-terminal residues 76–93 and 204–218. Anti-gC1qR mAbs 60.11, 46.23, and 74.5.2 inhibit this interaction, and co-immunoprecipitation of Raji cell membranes with anti-gC1qR mAbs co-precipitates cC1qR.\",\n      \"method\": \"Solid-phase ELISA with biotinylated cC1qR and recombinant gC1qR, antibody inhibition, co-immunoprecipitation from cell membranes\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ELISA binding + Co-IP from cell membranes + domain mapping, single lab\",\n      \"pmids\": [\"9233640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"gC1qR binds the C-terminal cytoplasmic domain of the alpha1B-adrenergic receptor (residues 344–516, specifically the arginine-rich residues 369–378) as identified by yeast two-hybrid; co-expression of gC1qR with the receptor causes redistribution of the receptor from plasma membrane to intracellular locations and receptor downregulation.\",\n      \"method\": \"Yeast two-hybrid screen of rat liver cDNA library, co-immunoprecipitation from COS-7 cells, confocal co-localization, deletion mutant mapping\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid, Co-IP, confocal, deletion mutant, single lab\",\n      \"pmids\": [\"10409668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HABP1/C1QBP is an endogenous substrate for MAP kinase (ERK); in vitro kinase assay demonstrates ERK phosphorylates HABP1, and HABP1 co-immunoprecipitates with activated ERK in cells. Upon PMA stimulation, HABP1 translocates from cytoplasm to nucleus in an ERK-dependent manner (blocked by PD98059).\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation with activated ERK, subcellular fractionation/immunofluorescence after PMA treatment, ERK inhibitor PD98059\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus Co-IP plus pharmacological inhibition confirming pathway, single lab\",\n      \"pmids\": [\"11866440\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Direct binding of HCV core protein to gC1qR on T cells impairs Lck and Akt activation; this binding is inhibitable by anti-gC1qR antibody or soluble gC1qR, is reduced by gC1qR siRNA knockdown, and enhanced by gC1qR transfection. BIAcore analysis gives binding affinity constant of 3.8×10−7 M.\",\n      \"method\": \"BIAcore surface plasmon resonance, flow cytometry binding, siRNA knockdown of gC1qR, transfection of guinea pig cells with human gC1qR, Western blot for Lck/ZAP-70/Akt phosphorylation\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SPR affinity measurement + siRNA loss-of-function + gain-of-function transfection + signaling readout, single lab\",\n      \"pmids\": [\"15163734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HCV core binding to gC1qR on T cells induces G0/G1 cell cycle arrest by stabilizing the CDK inhibitor p27Kip1, thereby preventing CDK2/4 and cyclin E/D expression, pRb phosphorylation, and G1→S transition; arrest is reversible by anti-gC1qR antibody.\",\n      \"method\": \"T-cell proliferation assay, flow cytometry cell cycle analysis, Western blot for CDK2/4, cyclin E/D, pRb, p27Kip1, antibody rescue experiment\",\n      \"journal\": \"Virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell cycle assay with antibody rescue + multiple molecular readouts, single lab\",\n      \"pmids\": [\"14517080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HCV core/gC1qR ligation on T cells induces SOCS1 and SOCS3 expression, which disrupts STAT phosphorylation and inhibits IFN-γ production; siRNA silencing of either SOCS1 or SOCS3 abrogates the inhibitory effect of core on T-cell IFN-γ production.\",\n      \"method\": \"T-cell functional assay, Western blot for SOCS1/3 and p-STAT, siRNA knockdown of SOCS1 and SOCS3, IFN-γ ELISA\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function confirming SOCS-mediated pathway, functional readout, single lab\",\n      \"pmids\": [\"16306613\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"gC1qR inhibits RIG-I- and MDA5-dependent antiviral signaling by translocating to the mitochondrial outer membrane upon dsRNA/virus stimulation and interacting with the adaptor VISA/MAVS/IPS-1/Cardif, thereby disrupting RIG-I/MDA5 signaling and promoting virus replication. Knockdown of gC1qR enhances RIG-I-dependent antiviral signaling.\",\n      \"method\": \"Co-immunoprecipitation (gC1qR with MAVS), siRNA knockdown, subcellular fractionation showing translocation, viral replication assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating interaction with MAVS, siRNA with functional antiviral readout, localization by fractionation, single lab with orthogonal methods\",\n      \"pmids\": [\"19164550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"MT1-MMP cleaves gC1qR proteolytically at Gly79↓Gln80 in vitro and in cell culture; the hemopexin-like domain of MT1-MMP is required for proteolysis. A catalytically inactive MT1-MMP retains gC1qR binding ability and acts as a cell-surface receptor for gC1qR.\",\n      \"method\": \"In vitro proteolysis assay with recombinant proteins, cell culture experiments, MT1-MMP domain deletion constructs, hydroxamate inhibitor studies, co-precipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro proteolysis with defined cleavage site + domain deletion constructs + cell culture validation, single lab\",\n      \"pmids\": [\"11773076\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"p32/gC1qR is required for mitochondrial translation; p32-knockout mice show mid-gestation lethality and severe respiratory chain dysfunction. Recombinant p32 binds mitochondrial mRNA (not DNA), endogenous p32 associates with all mitochondrial mRNA species in vivo, and co-immunoprecipitation shows p32 associates with the mitoribosome.\",\n      \"method\": \"p32-knockout mouse generation, primary embryonic fibroblast analysis, in vitro RNA-binding assay, co-immunoprecipitation with mitoribosome, mitochondrial respiratory chain assays\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — knockout mouse phenotype + in vitro RNA-binding reconstitution + mitoribosome Co-IP + multiple respiratory chain readouts, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22904065\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Plasmodium falciparum-infected red blood cells use gC1qR/HABP1/p32 as a receptor to bind to human brain microvascular endothelial cells and to platelets for clumping, as demonstrated by in vitro cytoadherence assays.\",\n      \"method\": \"In vitro cytoadherence assay on cells expressing gC1qR, blocking with anti-gC1qR antibodies and recombinant gC1qR\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cytoadherence assay with antibody blocking, single lab\",\n      \"pmids\": [\"17907801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Cell-surface gC1qR is required for growth factor-induced lamellipodia formation and cell migration; gC1qR is concentrated in lamellipodia with CD44, monosialoganglioside, actin, and phospho-FAK, and gC1qR depletion reduces FAK activation, receptor tyrosine kinase activation, lamellipodia formation, cell migration, and in vivo metastasis.\",\n      \"method\": \"siRNA knockdown, immunofluorescence co-localization in lamellipodia, Western blot for FAK/RTK phosphorylation, migration assay, xenograft mouse model\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with multiple readouts (signaling, migration, in vivo metastasis), single lab\",\n      \"pmids\": [\"21536672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Soluble gC1qR binds to endothelial cells via residues 174–180, with binding mediated through surface-bound fibrinogen; this binding induces upregulation of bradykinin receptor B1R expression, an effect diminished by gC1qR lacking residues 174–180 and 154–162 and inhibited by anti-fibrinogen antibody.\",\n      \"method\": \"Solid-phase binding assay, deconvolution fluorescence microscopy, flow cytometry for B1R expression, deletion mutant analysis, antibody inhibition\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain mapping with deletion mutants + functional receptor upregulation assay, single lab\",\n      \"pmids\": [\"24319267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"gC1q-R/GABA(A) receptor beta subunit interaction: gC1qR co-purifies with immunopurified GABA(A) receptors and exhibits reciprocal co-immunoprecipitation from rat brain membranes. Yeast two-hybrid showed all beta subunits (but not alpha1 or gamma2) interact with gC1qR via a 15-amino-acid stretch (residues 399–413) containing 7 positively charged residues.\",\n      \"method\": \"Immunopurification from bovine brain, mass spectrometric identification, reciprocal Co-IP from rat brain membranes, yeast two-hybrid with deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP from native brain tissue + yeast two-hybrid domain mapping, single lab\",\n      \"pmids\": [\"11350968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Biallelic loss-of-function mutations in C1QBP cause combined respiratory-chain enzyme deficiency of complexes I, III, and IV; complementation of C1qbp−/− MEFs with wild-type but not mutagenized C1qbp restores OXPHOS protein levels and mitochondrial enzyme activities, establishing C1QBP as essential for mitochondrial energy metabolism.\",\n      \"method\": \"Patient genetics, C1qbp−/− MEF complementation assay (wild-type vs. mutant), respiratory chain enzyme activity assays, OXPHOS complex protein levels\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — complementation rescue with wild-type vs. mutant in knockout MEFs + biochemical enzyme assays + replicated across multiple unrelated families\",\n      \"pmids\": [\"28942965\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Cardiomyocyte-specific deletion of p32/C1qbp causes contractile dysfunction, cardiac dilatation, fibrosis, decreased COX1 expression, reduced oxygen consumption, and increased oxidative stress. p32-deficient hearts show constitutive AMPK phosphorylation, reduced mTOR signaling, increased FGF21/integrated stress response, and impaired urea cycle, with median lifespan ~14 months.\",\n      \"method\": \"Cre-loxP cardiac-specific knockout, echocardiography, electron microscopy of mitochondria, Western blot for AMPK/mTOR/signaling proteins, metabolic analysis, Seahorse respirometry\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — tissue-specific knockout with multiple functional, ultrastructural, and metabolic readouts, comprehensive mechanistic characterization\",\n      \"pmids\": [\"28498888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"p32/C1qbp interacts with the E2 component of the pyruvate dehydrogenase (PDH) complex (dihydrolipoamide S-acetyltransferase, DLAT) and positively regulates PDH activity; p32-deficient DCs show impaired LPS-induced citrate increase, and PDH inhibitor reproduces the p32-null phenotype of decreased DC maturation in vivo.\",\n      \"method\": \"Co-immunoprecipitation of p32 with DLAT, PDH activity assay in p32-deficient DCs, metabolic analysis, PDH inhibitor in vivo study in p32-null mice\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + enzymatic activity assay + pharmacological phenocopy in vivo, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"30428349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Subcellular fractionation combined with Co-IP-MS identified DLAT (dihydrolipoyllysine-residue acetyltransferase, E2 subunit of PDH complex) as a novel mitochondrial interacting partner of C1QBP; PDH activity is affected by C1QBP expression level.\",\n      \"method\": \"Subcellular fractionation coupled with Co-IP and mass spectrometry, validation by Co-IP/Western blot, PDH activity assay\",\n      \"journal\": \"Analytical and bioanalytical chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP-MS with enzymatic activity validation, single lab\",\n      \"pmids\": [\"26753982\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"C1QBP forms a complex (MRC) with MRE11 and RAD50 that stabilizes MRE11/RAD50 but inhibits MRE11 nuclease activity by preventing DNA/chromatin binding. Upon DNA double-strand breaks, ATM phosphorylates MRE11 at S676/S678, dissociating the MRC and allowing MRN complex assembly and recruitment to DSBs; either excess or insufficient C1QBP impairs DSB repair.\",\n      \"method\": \"Co-immunoprecipitation, MRE11 nuclease activity assay, chromatin fractionation, ATM kinase assay, phosphorylation site mutagenesis, C1QBP knockdown/overexpression with DSB response readouts\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — Co-IP + nuclease activity assay + phospho-mutagenesis + chromatin recruitment assay + multiple genetic perturbations, comprehensive mechanistic study\",\n      \"pmids\": [\"31353207\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"C1QBP interacts with YBX1 and negatively regulates YBX1 activation; C1QBP knockdown enhances YBX1 phosphorylation and nuclear translocation in renal cell carcinoma.\",\n      \"method\": \"Co-immunoprecipitation followed by mass spectrometry, validation by IP/Western blot, siRNA knockdown of C1QBP, nuclear fractionation\",\n      \"journal\": \"Journal of proteome research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP-MS with functional validation (siRNA + nuclear translocation), single lab\",\n      \"pmids\": [\"25497084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"C1QBP interacts with YBX1 and suppresses YBX1 activation by altering YBX1 phosphorylation and nuclear translocation in RCC cells; this suppresses AR-modulated MMP9 signaling to inhibit cell invasion, confirmed in orthotopic in vivo mouse model.\",\n      \"method\": \"Co-immunoprecipitation, Western blot for YBX1 phosphorylation and nuclear translocation, siRNA/overexpression functional assays, orthotopic mouse model\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"28107702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ZNF32 transcriptionally activates C1QBP expression; C1QBP is a direct target gene of ZNF32 that inactivates the p38 MAPK pathway to protect against oxidative stress-induced apoptosis. ZNF32-deficient cells show reduced C1QBP and increased p38 MAPK activation.\",\n      \"method\": \"Chromatin immunoprecipitation (ZNF32 binding to C1QBP promoter), ZNF32 knockdown/overexpression with C1QBP and p38 MAPK readouts, luciferase promoter assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrating direct transcriptional regulation + functional knockdown assays, single lab\",\n      \"pmids\": [\"26497555\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The FXII fibronectin type II (FnII) domain binds gC1qR in a Zn2+-dependent, asymmetric fashion on the gC1qR trimer; crystal structure of the FXIIFnII–gC1qR complex reveals Arg36 and Arg65 of FXII contact two distinct negatively charged pockets of gC1qR. gC1qR residues Asp185 and His187 coordinate Zn2+ adjacent to the FXII-binding site; binding induces allosteric ordering of the anionic G1-loop. HK domain 5 (HKD5) binds only one high-affinity site per gC1qR trimer via a central G3-loop (steric occlusion mechanism). gC1qR clusters FXII and HK into a ~500 kDa ternary complex and stimulates coagulation in a FXII-dependent manner.\",\n      \"method\": \"Crystal structure determination, SPR with mutagenesis, gel filtration for ternary complex, plasma-based FXII-dependent coagulation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis validated by SPR plus functional plasma coagulation assay, comprehensive multi-method study\",\n      \"pmids\": [\"32559765\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C1qbp is intrinsically required for effector CD8+ T cell differentiation; C1qbp-deficient CD8+ T cells fail to increase mitochondrial respiratory capacity upon activation, resulting in diminished acetyl-CoA and elevated fumarate and 2-hydroxyglutarate, leading to H3K27 hypoacetylation and hypermethylation and transcriptional silencing of effector genes. Fumarate supplementation or HDAC inhibitor + acetate reversed the differentiation defect.\",\n      \"method\": \"Conditional C1qbp knockout in CD8+ T cells, metabolomics, histone modification analysis (ChIP), Seahorse respirometry, viral infection models, pharmacological rescue\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with metabolomics + epigenetic analysis + pharmacological rescue, comprehensive mechanistic characterization, single lab\",\n      \"pmids\": [\"34860557\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Active caspase-1 cleaves gC1qR at two caspase-1 cleavage sites, preventing mitochondrial import of gC1qR; this results in aerobic glycolysis (Warburg effect) and enhanced cell proliferation. Non-mitochondrial gC1qR localization correlated with caspase-1 activation and tumor grade in colorectal carcinoma patients.\",\n      \"method\": \"Caspase-1 cleavage assay in vitro, mitochondrial import assay, metabolic profiling of glycolysis/OXPHOS, cell proliferation assay, immunohistochemistry correlation in patient tumors\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro cleavage assay + mitochondrial import assay + metabolic readout, single lab\",\n      \"pmids\": [\"33102234\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"gC1qR binds directly to the D domain of fibrinogen/fibrin (specifically the C-terminal segment of the fibrinogen gamma chain in fragment D-100, lost upon further plasmin digestion to D-60) and inhibits fibrin polymerization in a dose-dependent manner; at 2:1 molar ratio (gC1qR:fibrinogen), fibrin clot formation is completely inhibited.\",\n      \"method\": \"Solid-phase ELISA with biotinylated gC1qR, fibrin polymerization turbidity assay, binding to fibrinogen degradation fragments\",\n      \"journal\": \"Clinical immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — reconstitution binding assay + functional fibrin polymerization inhibition + domain mapping, single lab\",\n      \"pmids\": [\"10075865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Soluble recombinant gC1qR (rgC1qR) enhances blood coagulation: it dose-dependently shortens prothrombin time and plasma recalcification time, with procoagulant activity measurable in factor XII- or factor XI-deficient plasma, suggesting activity not exclusively through the contact system.\",\n      \"method\": \"Prothrombin time assay in human plasma, plasma recalcification time assay, factor-deficient plasma studies, chromogenic substrate assays for thrombin and factor Xa\",\n      \"journal\": \"Blood coagulation & fibrinolysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional plasma coagulation assays with recombinant protein, multiple coagulation pathway dissection, single lab\",\n      \"pmids\": [\"9607116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Exosomal CD44v6/C1QBP complex from pancreatic cancer cells is delivered to the plasma membrane of hepatic stellate cells (HSCs), leading to phosphorylation of IGF-1 signaling molecules, HSC activation, and liver fibrosis promoting metastasis. C1QBP knockdown suppresses this effect in vitro and in vivo.\",\n      \"method\": \"Exosome isolation, stable lentiviral knockdown/overexpression, mouse liver metastasis models, Western blot for IGF-1R phosphorylation, HSC activation markers\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockdown/overexpression in multiple in vivo models + signaling readouts, single lab\",\n      \"pmids\": [\"33827783\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"C1QBP in lipid rafts is required for IGF-1-induced hepatic metastasis of pancreatic cancer; IGF-1 triggers translocation of C1QBP from cytoplasm to lipid rafts and formation of a CD44v6/C1QBP complex, which promotes IGF-1R phosphorylation and downstream PI3K/MAPK signaling. C1QBP knockdown suppresses hepatic metastasis in nude mice.\",\n      \"method\": \"Lipid raft fractionation, Co-IP of CD44v6 and C1QBP, Western blot for IGF-1R/PI3K/MAPK phosphorylation, siRNA knockdown, hepatic metastasis mouse model\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lipid raft fractionation + Co-IP + in vivo knockdown model, single lab\",\n      \"pmids\": [\"28608366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HABP1/gC1qR forms a noncovalently associated homotrimer in equilibrium with a covalently linked hexamer (dimer of trimers) through disulfide bonds at Cys186; the hexameric form shows enhanced affinity for hyaluronan, gC1q, and mannosylated BSA compared with the trimer.\",\n      \"method\": \"Size-exclusion chromatography, glutaraldehyde cross-linking, fluorescence spectroscopy with Hg2+, Cys186 chemical modification, ligand-binding assays comparing trimer vs. hexamer\",\n      \"journal\": \"European journal of biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical characterization with mutagenesis (Cys186 modification) and multiple ligand-binding comparisons, single lab\",\n      \"pmids\": [\"11784324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"DC-SIGN, C1q, and gC1qR form a trimolecular receptor complex on immature dendritic cells; DC-SIGN binds directly to C1q (and its globular domain) in a Ca2+-dependent manner at its mannose-binding pocket, and C1q/gC1qR associate with DC-SIGN on blood DC precursors and immature DCs by immunofluorescence and antigen-capture ELISA.\",\n      \"method\": \"ELISA, flow cytometry, immunoprecipitation, surface plasmon resonance, immunofluorescence microscopy, mannan competition, calcium chelation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SPR + Co-IP + ELISA + imaging, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"22700724\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"C1QBP directly interacts with the C9-ALS-associated proline-arginine dipeptide repeat protein (PR50); C1QBP knockdown in HMC3 microglial cells induces NLRP3 inflammasome activation similar to PR50 expression. The compound syringin blocks the PR50-C1QBP interaction and reduces PR50-induced NLRP3 inflammasome activation.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown of C1QBP, NLRP3 inflammasome activity assay, syringin treatment/competitive inhibition\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP + siRNA knockdown, single lab, limited mechanistic depth\",\n      \"pmids\": [\"36231090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"HABP1/gC1qR localizes to the Golgi apparatus and disperses throughout the cell during mitosis, resembling the distribution dynamics of its ligand hyaluronan.\",\n      \"method\": \"Indirect immunofluorescence with Golgi and mitochondrial markers across cell cycle stages\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — immunofluorescence localization without functional consequence demonstrated, single lab\",\n      \"pmids\": [\"15780180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Mutational analysis of C1q globular head modules revealed that Arg162 of the ghA module is central to C1q-gC1qR interaction, while an Arg114Glu substitution in ghB enhanced binding; ghA, ghB, and ghC each independently bind gC1qR and attenuate PHA-stimulated PBMC proliferation.\",\n      \"method\": \"Recombinant globular head module expression, substitution mutagenesis, ELISA binding assays, cell proliferation assay\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-directed mutagenesis + binding assays + functional proliferation assay, single lab\",\n      \"pmids\": [\"28018340\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"C1QBP (p32/gC1qR/HABP1) is a homotrimeric, multifunctional protein that resides primarily in the mitochondrial matrix—where it binds mitochondrial mRNAs, associates with the mitoribosome, and interacts with the PDH complex E2 subunit (DLAT) to support mitochondrial translation and oxidative phosphorylation—but also traffics to other compartments where it serves as a multiligand docking platform: on cell surfaces it binds C1q, HK, FXII (zinc-dependently, via a defined crystal structure), vitronectin, fibrinogen, InlB, HCV core, S. aureus protein A, and numerous other ligands to modulate complement, kinin, coagulation, and antiviral (MAVS/RIG-I) signaling; it also forms a nuclear complex with MRE11/RAD50 that is dissociated by ATM-mediated phosphorylation to control homologous recombination, interacts with YBX1 to suppress oncoprotein signaling, acts as a substrate for ERK (translocating to the nucleus upon mitogenic stimulation), and can be cleaved by caspase-1 to prevent mitochondrial import and redirect metabolism toward aerobic glycolysis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"C1QBP (p32/gC1qR/HABP1) is a homotrimeric multifunctional protein whose primary residence is the mitochondrial matrix, where it supports mitochondrial gene expression and energy metabolism, but which also operates as a multiligand docking platform across the cell surface, cytoplasm, and nucleus [#0, #17, #30]. An N-terminal presequence directs import into the mitochondrial matrix, where the mature protein binds mitochondrial mRNAs and associates with the mitoribosome to drive mitochondrial translation; loss of C1QBP causes mid-gestation lethality and severe respiratory-chain dysfunction in mice, and biallelic loss-of-function mutations in humans cause combined deficiency of OXPHOS complexes I, III, and IV [#0, #17, #22]. Within the matrix it binds the PDH E2 subunit DLAT and positively regulates pyruvate dehydrogenase activity, linking it to acetyl-CoA supply, and tissue-specific deletion produces cardiac contractile failure with AMPK activation and integrated stress responses while CD8+ T-cell-specific loss impairs effector differentiation through metabolite-driven histone hypoacetylation and hypermethylation [#24, #25, #23, #31]. The protein assembles as a trimer in equilibrium with a disulfide-linked hexamer, and a crystal structure of the FXII fibronectin type II domain bound to the gC1qR trimer defines the zinc-dependent, asymmetric binding chemistry by which it clusters FXII and high-molecular-weight kininogen into a procoagulant ternary complex on endothelial cells together with uPAR and cytokeratin 1 [#37, #30, #6, #2]. Through spatially distinct binding sites it engages an extensive ligand repertoire — C1q, vitronectin, fibrinogen, and microbial proteins including Listeria InlB, HCV core, and S. aureus protein A — to modulate complement, kinin, coagulation, and host-pathogen interactions [#1, #2, #3, #4, #5, #33, #41]. C1QBP additionally restrains innate antiviral signaling by translocating to the mitochondrial outer membrane and binding MAVS to suppress RIG-I/MDA5 responses, forms a nuclear complex with MRE11/RAD50 (the MRC) that is dissociated by ATM-mediated MRE11 phosphorylation to license homologous-recombination repair, and acts as an ERK substrate that relocates to the nucleus upon mitogenic stimulation [#15, #26, #11]. In cancer it interacts with YBX1 to suppress oncogenic invasion signaling, and caspase-1 cleavage prevents its mitochondrial import to redirect metabolism toward aerobic glycolysis [#27, #28, #32].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established that gC1qR is a cell-surface receptor whose ligand-binding repertoire extends beyond C1q, defining anatomically distinct binding sites for vitronectin and for the contact-system proteins HK and factor XII.\",\n      \"evidence\": \"Affinity chromatography of endothelial membranes and recombinant protein binding assays with truncation/inhibition mapping\",\n      \"pmids\": [\"8900153\", \"8710908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of distinct ligand sites not resolved\", \"Physiological relevance of cell-surface display from a mitochondrial protein not addressed\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated that gC1qR physically associates with calreticulin (cC1qR), an early hint that it acts as a scaffold forming multiprotein receptor complexes rather than a lone receptor.\",\n      \"evidence\": \"Solid-phase ELISA, domain mapping, and Co-IP from cell membranes\",\n      \"pmids\": [\"9233640\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the cC1qR/gC1qR complex unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the dual localization paradox by identifying an N-terminal mitochondrial targeting presequence directing the protein to the matrix, while also showing soluble recombinant protein has procoagulant activity in plasma.\",\n      \"evidence\": \"GFP-presequence fusion, mitoplast fractionation, and plasma coagulation assays\",\n      \"pmids\": [\"9531316\", \"9607116\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which a matrix protein reaches the cell surface unexplained\", \"Molecular basis of procoagulant activity not defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Extended the coagulation/kinin role by mapping gC1qR binding to the HK light chain and to the fibrinogen D domain, where it inhibits fibrin polymerization, positioning the protein at multiple nodes of the contact and clotting systems.\",\n      \"evidence\": \"Affinity chromatography with domain peptides, fibrin turbidity assays, and antibody inhibition\",\n      \"pmids\": [\"10479529\", \"10075865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo relevance of fibrin inhibition versus procoagulant activity unreconciled\", \"Single lab\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Revealed gC1qR as a hijacked microbial receptor, serving as the direct entry receptor for Listeria InlB (recruiting Gab1/PI3K), binding HCV core to suppress T cells, and binding S. aureus protein A.\",\n      \"evidence\": \"Yeast two-hybrid, affinity chromatography, gain-of-function transfection entry assays, and Co-IP\",\n      \"pmids\": [\"10747014\", \"11086025\", \"10722602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How surface gC1qR transduces signals lacking a transmembrane domain unresolved\", \"Receptor partners required for signaling incompletely defined\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Defined the endothelial contact-system receptor complex (gC1qR/uPAR/cytokeratin 1) that binds and activates factor XII/prekallikrein zinc-dependently, and identified gC1qR as an ERK substrate that translocates to the nucleus, linking it to mitogenic signaling and to GABA(A) receptor beta subunits in brain.\",\n      \"evidence\": \"Flow cytometry/EM co-localization, purified-protein activation assays, in vitro kinase assay with PD98059, and reciprocal Co-IP from brain\",\n      \"pmids\": [\"11986212\", \"11204562\", \"11866440\", \"11350968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of nuclear translocation not defined\", \"GABA(A) interaction physiology unexplored\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Characterized the quaternary structure, showing the protein equilibrates between a noncovalent trimer and a disulfide-linked hexamer (via Cys186) with the hexamer exhibiting enhanced ligand affinity.\",\n      \"evidence\": \"Size-exclusion chromatography, cross-linking, Cys186 modification, and comparative ligand binding\",\n      \"pmids\": [\"11784324\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo prevalence of hexamer not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified an immunoregulatory mechanism whereby gC1qR translocates to the mitochondrial outer membrane and binds MAVS to dampen RIG-I/MDA5 antiviral signaling, promoting viral replication.\",\n      \"evidence\": \"Co-IP with MAVS, siRNA knockdown with antiviral readouts, and fractionation showing translocation\",\n      \"pmids\": [\"19164550\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stimulus-driven trafficking mechanism to outer membrane unresolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established the core mitochondrial function: C1QBP binds mitochondrial mRNAs and the mitoribosome and is essential for mitochondrial translation, with knockout causing embryonic lethality and respiratory-chain failure.\",\n      \"evidence\": \"p32-knockout mouse, in vitro RNA-binding assays, and mitoribosome Co-IP\",\n      \"pmids\": [\"22904065\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specificity/mechanism of mRNA binding not structurally defined\", \"Role at the mitoribosome step not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Cemented C1QBP as essential for human and tissue energy metabolism through disease genetics, complementation rescue, and a cardiomyocyte knockout linking its loss to OXPHOS failure, AMPK activation, and integrated stress responses.\",\n      \"evidence\": \"Patient genetics with C1qbp-/- MEF complementation (WT vs mutant), enzyme assays, and Cre-loxP cardiac knockout with respirometry\",\n      \"pmids\": [\"28942965\", \"28498888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype spectrum of human mutations incompletely mapped\", \"Tissue-specific vulnerability determinants unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected C1QBP directly to central carbon metabolism by identifying the PDH E2 subunit DLAT as a mitochondrial partner and showing C1QBP positively regulates PDH activity.\",\n      \"evidence\": \"Subcellular fractionation Co-IP-MS with PDH activity validation, later extended with dendritic-cell knockout and PDH-inhibitor phenocopy\",\n      \"pmids\": [\"26753982\", \"30428349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether C1QBP regulates PDH directly or via translation of components unresolved\", \"Stoichiometry of DLAT interaction undefined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined a nuclear genome-stability role: C1QBP forms the MRC complex with MRE11/RAD50 that holds MRE11 nuclease inactive until ATM phosphorylates MRE11 to dissociate the complex and license MRN-mediated DSB repair.\",\n      \"evidence\": \"Co-IP, nuclease activity assays, ATM kinase assay, phospho-site mutagenesis, and chromatin recruitment with genetic perturbation\",\n      \"pmids\": [\"31353207\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nuclear C1QBP pool is established relative to mitochondrial pool unclear\", \"Dosage-sensitivity mechanism not fully defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Demonstrated that C1QBP-dependent mitochondrial metabolism drives epigenetic programming of immune cell fate, with CD8+ T-cell loss causing metabolite imbalances that silence effector genes via histone modification changes.\",\n      \"evidence\": \"Conditional knockout with metabolomics, ChIP histone-modification analysis, respirometry, and pharmacological rescue\",\n      \"pmids\": [\"34860557\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality across other immune lineages unestablished\", \"Direct chromatin targets of the metabolite shift not enumerated\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Provided the structural mechanism for contact-system clustering, showing zinc-dependent asymmetric binding of FXII and HK on the gC1qR trimer to form a procoagulant ~500 kDa ternary complex.\",\n      \"evidence\": \"Crystal structure of FXIIFnII-gC1qR, SPR with mutagenesis, gel filtration, and plasma coagulation assay\",\n      \"pmids\": [\"32559765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of other ligand interactions still lacking\", \"Physiological control of surface clustering in vivo unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How C1QBP partitions between mitochondrial, surface, cytoplasmic, and nuclear pools — and what governs the trafficking decisions that switch it between metabolic, signaling, repair, and receptor functions — remains the central unresolved question.\",\n      \"evidence\": \"No single study reconciles the compartment-switching mechanism\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for trafficking of a presequence-bearing matrix protein to the cell surface\", \"Regulatory logic selecting among its functions per compartment unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [17]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 6, 30, 38]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [24, 26, 33]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [3, 4, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0, 17, 22, 23]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 6, 19, 36]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [11, 26]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [11, 27]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [17, 22, 24, 31]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [6, 30, 33, 34]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 31, 41]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [26]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [\n      \"MRE11/RAD50 (MRC)\",\n      \"gC1qR/uPAR/cytokeratin 1 contact-system receptor\",\n      \"mitoribosome\",\n      \"DC-SIGN/C1q/gC1qR\"\n    ],\n    \"partners\": [\n      \"DLAT\",\n      \"MRE11\",\n      \"RAD50\",\n      \"MAVS\",\n      \"YBX1\",\n      \"C1q\",\n      \"F12\",\n      \"CD44\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}