C1QC

C1QC encodes the C-chain subunit of the C1q complement complex, and its expression is required for circulating C1q and a functional classical complement pathway; compound heterozygous loss-of-function mutations abolish serum C1q protein (PMID:31357913). Beyond its canonical complement role, C1QC functions as a tissue-context effector in inflammation, immunosuppression, and matrix remodeling. In tumor microenvironments, C1QC is induced downstream of FAP+ fibroblast-derived WNT2/β-catenin signaling in macrophages, where it maintains M2 identity (CD163), enhances fatty acid metabolism and immunosuppressive signaling, and promotes tumor cell proliferation and drug resistance (PMID:39388888, PMID:41831519). C1QC also drives pathology under metabolic and ischemic stress: it binds DDR2 to activate MMP9-mediated extracellular matrix degradation and blood-brain barrier disruption under diabetic conditions (PMID:39531193), acts as a direct target of the circDnajc1/miR-27a-5p axis to govern microglial inflammatory output and neuronal apoptosis (PMID:40483386), and lies downstream of metabolic stress to promote lipid accumulation and inflammation in renal tubular epithelial cells (PMID:41252098). Structural and biochemical detail of the C1QC-DDR2 interaction has not been resolved in the available corpus.

1. 2019 Medium

   Established that C1QC is genetically required for circulating C1q, resolving whether the C-chain subunit is essential for classical complement pathway function.

   Evidence Compound heterozygous mutation analysis with ELISA/Western blot for serum C1q and RNA sequencing to confirm trans configuration in a patient

   PMID:31357913

   Open questions at the time

   • Single case report; not corroborated across an independent cohort
   • Does not address non-complement functions of C1QC
   • Mechanism by which subunit loss destabilizes the C1q hexamer not biochemically dissected
2. 2024 Medium

   Identified a non-complement effector role for C1QC in barrier pathology by linking it to DDR2 binding and MMP9-driven matrix degradation under diabetic stress.

   Evidence siRNA knockdown in vitro and in vivo diabetic models, Western blot for MMP9 activation, and a C1QC-DDR2 binding assay

   PMID:39531193

   Open questions at the time

   • No structural validation or reconstitution of direct C1QC-DDR2 binding
   • Whether MMP9 activation is direct or indirect not resolved
   • Single lab
3. 2024 Medium

   Placed C1qc within a circDnajc1/miR-27a-5p regulatory axis controlling microglial inflammation, answering how C1qc expression is post-transcriptionally tuned in ischemic injury.

   Evidence circDnajc1 knockdown/overexpression in OGD/R cells and MCAO/R rats with RNA immunoprecipitation and luciferase reporter assays establishing C1qc as a miR-27a-5p target

   PMID:40483386

   Open questions at the time

   • Functional contribution of C1qc versus co-regulated C3/C5ar not separated
   • Rodent ortholog model; human relevance not confirmed
   • Single lab
4. 2025 Medium

   Demonstrated that C1QC maintains M2 macrophage identity and tumor-promoting macrophage-lymphoma interactions, establishing a cell-autonomous immunomodulatory function.

   Evidence siRNA knockdown with WB/qPCR for CD163 and macrophage-lymphoma co-culture proliferation and drug-sensitivity assays

   PMID:39388888

   Open questions at the time

   • Molecular mechanism by which C1QC sustains CD163/M2 state unknown
   • No in vivo tumor model in this study
   • Single lab
5. 2025 Medium

   Defined an upstream signaling axis (FAP+ fibroblast WNT2→β-catenin) driving C1QC induction in immunosuppressive macrophages, connecting stromal signaling to C1QC+ macrophage function.

   Evidence Co-culture, single-cell RNA-seq, spatial transcriptomics, and in vivo OSCC model with FAP inhibition

   PMID:41831519

   Open questions at the time

   • Direct transcriptional control of C1QC by β-catenin not shown at promoter level
   • Relative contribution of C1QC to the immunosuppressive phenotype versus correlation not fully isolated
   • Single lab
6. 2025 Medium

   Positioned C1QC downstream of metabolic stress and upstream of renal lipid accumulation and inflammation, providing epistatic placement via drug rescue.

   Evidence siRNA knockdown and overexpression in HK-2 cells, db/db mouse model, and empagliflozin co-treatment rescue with lipid/inflammatory readouts

   PMID:41252098

   Open questions at the time

   • Direct molecular targets of C1QC in tubular cells not identified
   • Whether effect is complement-dependent unresolved
   • Single lab
7. 2024 Low

   Reported a direct antiviral activity for the C1qC protein in a teleost ortholog, extending innate-immune function beyond mammals.

   Evidence Recombinant grass carp C1qC incubation with CIK cells followed by GCRV infection and viral replication quantification

   PMID:38447782

   Open questions at the time

   • Single functional assay with recombinant protein; no mutagenesis or mechanistic follow-up
   • Non-mammalian ortholog; relevance to human C1QC unestablished
   • Mechanism of viral inhibition unknown

• How the secreted complement subunit C1QC mechanistically transitions to a cell-intrinsic driver of macrophage polarization, matrix degradation, and metabolic inflammation across tissues remains unresolved.
• No structural model of C1QC partner interactions (e.g. DDR2)
• Unclear whether tissue phenotypes are complement-dependent or complement-independent
• Direct transcriptional and signaling control of C1QC induction not defined at the promoter level