CFB

CFB (complement factor B) encodes the catalytic subunit of the alternative pathway C3 convertase (C3bBb), a serine protease that is cleaved by factor D into Ba and Bb fragments upon binding C3b, with the Bb fragment providing the proteolytic activity that cleaves C3 and C5 to propagate complement activation (PMID:9780182). This domain architecture—comprising complement control protein (CCP) domains, a von Willebrand factor type A domain mediating C3b interaction, and a C-terminal serine protease domain—is deeply conserved across vertebrates (PMID:17482263). A loss-of-function variant (G252S) that introduces a de novo glycosylation site impairs C3b binding and factor D-mediated cleavage, reducing complement-driven macrophage phagocytosis and cytokine secretion (PMID:37080587). In diabetic kidney disease, CFB deficiency attenuates tubulointerstitial injury by blocking C3 activation and downstream NF-κB p65-mediated transcription of ceramide synthase genes, linking alternative pathway signaling to lipid-mediated tissue damage (PMID:36546481).

1. 1991 Medium

   Establishing that naturally occurring CFB allotypes (BF F vs. BF S) differ in intrinsic hemolytic activity showed that structural polymorphisms within CFB itself modulate complement functional output, independent of protein concentration.

   Evidence Allele-specific hemolytic activity and crossed immunoelectrophoresis in human samples with MHC haplotype analysis

   PMID:1916952

   Open questions at the time

   • The specific amino acid differences responsible for allotype-dependent activity differences were not identified
   • No structural or binding data explaining the reduced hemolytic efficiency of the F allotype
2. 1998 High

   Reconstitution of the alternative pathway C3 convertase from purified trout factor B, C3, and factor D demonstrated that CFB cleavage into Ba- and Bb-like fragments and subsequent convertase assembly is an evolutionarily conserved catalytic mechanism.

   Evidence In vitro C3 convertase reconstitution with purified components and hemolytic restoration assay in Bf-depleted trout serum

   PMID:9780182

   Open questions at the time

   • The precise structural determinants of C3b–Bb interaction were not resolved
   • Kinetic parameters of trout vs. mammalian convertase were not compared
3. 2007 Medium

   Cloning of nurse shark Bf/C2 established the deep conservation of CFB domain architecture (CCP–VWF-A–serine protease with a factor D cleavage site), anchoring the structural requirements for convertase catalytic function across jawed vertebrates.

   Evidence cDNA cloning, domain architecture analysis, and tissue expression profiling in nurse shark

   PMID:17482263

   Open questions at the time

   • No enzymatic activity or convertase assembly was directly demonstrated for the shark protein
   • Functional divergence between Bf and C2 paralogs at the activity level was not tested
4. 2022 High

   Demonstrating that CFB deficiency protects against diabetic kidney injury by blocking C3 activation, NF-κB p65-driven ceramide synthase transcription, and ceramide accumulation revealed a downstream effector pathway linking alternative complement activation to lipotoxic tissue damage.

   Evidence Cfb-knockout diabetic mice; siRNA knockdown in HK-2 cells under high glucose; C3 siRNA epistasis; exogenous ceramide rescue and CERS inhibitor experiments

   PMID:36546481

   Open questions at the time

   • Whether this ceramide-mediated pathway operates in non-renal tissues is unknown
   • The complement activation product (C3a, C5a, or MAC) responsible for triggering NF-κB was not identified
5. 2023 High

   Identifying that the G252S variant creates a de novo N-glycosylation site that impairs C3b binding and factor D cleavage provided a precise molecular explanation for loss-of-function complement deficiency and reduced macrophage effector activity in patients.

   Evidence Recombinant protein binding/cleavage assays with site-directed mutagenesis; flow cytometry–based macrophage phagocytosis; patient serum functional validation

   PMID:37080587

   Open questions at the time

   • Structural visualization (e.g., cryo-EM) of the glycosylated variant bound to C3b is lacking
   • The full clinical spectrum of G252S homozygosity beyond the reported pCD cohort is not defined

• A high-resolution structural basis for how specific CFB polymorphisms modulate convertase assembly kinetics and substrate specificity (C3 vs. C5) remains unresolved.
• No atomic-resolution structure of allotype-specific or glycosylation-mutant CFB in complex with C3b has been reported in this literature
• The identity of the downstream complement effector (C3a/C5a/MAC) driving NF-κB activation in kidney tubular cells is unknown
• Whether CFB proteolytic activity has substrates beyond C3 and C5 has not been explored