CFB

Complement Factor B (CFB) is the catalytic subunit of the alternative pathway C3 convertase, an evolutionarily ancient component of innate immune complement activation (PMID:9780182). CFB assembles with C3b and, upon cleavage by factor D into Ba and Bb fragments, forms the active convertase that drives C3-dependent complement amplification (PMID:9780182). The domain architecture underlying this function — short consensus repeats (SCRs/CCPs), a von Willebrand factor A domain, and a C-terminal serine protease domain bearing the factor D cleavage site — is deeply conserved across vertebrates (PMID:17482263). Beyond its classical role in opsonization, CFB acts upstream of C3 to activate NF-κB signaling, which induces the ceramide synthase CERS3 and ceramide biosynthesis in renal tubular cells, linking complement activation to ER stress, oxidative stress, and apoptosis in diabetic tubulointerstitial injury (PMID:36546481). CFB variants alter complement function in human disease: a gain-of-function mutation (p.Lys533Arg) is associated with atypical hemolytic uremic syndrome through dysregulated alternative pathway activation (PMID:20108004), while the G252S substitution generates a de novo glycosylation site that reduces C3b binding, impairs CFB cleavage, and diminishes complement-driven macrophage phagocytosis in perianal Crohn's disease (PMID:37080587).

1. 1991 Medium

   Established that allelic variation in CFB produces functional differences in complement activation, showing the protein's activity is not uniform across the population.

   Evidence Hemolytic overlay assay with protein quantitation and HLA haplotyping of human BF F and S allotypes

   PMID:1916952

   Open questions at the time

   • Molecular basis of the F/S activity difference not defined
   • Single study without structural follow-up
2. 1996 Medium

   Resolved the evolutionary origin of CFB by showing a single ancestral Bf/C2 gene with conserved exon-intron organization predates the mammalian Bf/C2 split.

   Evidence cDNA cloning, genomic mapping, and sequence analysis of the medaka Bf/C2 gene

   PMID:8824158

   Open questions at the time

   • Functional convertase activity of the ancestral molecule not tested
3. 1998 High

   Directly demonstrated that CFB is the catalytic serine protease subunit of the alternative pathway C3 convertase, defining its core enzymatic role.

   Evidence In vitro C3 convertase reconstitution with purified trout Bf, C3, factor D and Mg2+-EGTA; hemolytic and cleavage assays

   PMID:9780182

   Open questions at the time

   • Carried out with trout orthologs; human enzymatic kinetics not addressed
   • Convertase decay/regulation not examined
4. 1998 Medium

   Clarified that teleost Bf gene duplications arose independently of the mammalian Bf/C2 duplication, refining the gene family's evolutionary history.

   Evidence Genomic PAC hybridization, cDNA screening, and phylogenetic analysis in zebrafish

   PMID:9874500

   Open questions at the time

   • No functional characterization of duplicated Bf products
5. 2004 Low

   Proposed the ancestral five-SCR state of the Bf/C2 family and a mechanism for SCR number evolution via exon deletion.

   Evidence cDNA cloning and RT-PCR splicing analysis of sea urchin SpBf isoforms

   PMID:15448941

   Open questions at the time

   • Splice variant proteins not functionally reconstituted
   • Relevance to vertebrate CFB activity not established
6. 2007 Medium

   Established that the modular domain architecture enabling CFB cleavage and convertase formation is conserved from cartilaginous fish.

   Evidence cDNA cloning, domain mapping, and phylogenetic analysis of nurse shark Bf/C2 genes

   PMID:17482263

   Open questions at the time

   • Cleavage at the predicted factor D site not experimentally verified
   • No functional convertase assay
7. 2010 Low

   Linked a CFB coding mutation to human disease, implicating gain-of-function alternative pathway dysregulation in atypical hemolytic uremic syndrome.

   Evidence Clinical genetic sequencing of CFB exons in an aHUS patient identifying p.Lys533Arg

   PMID:20108004

   Open questions at the time

   • This specific mutation not functionally validated in vitro
   • Single patient observation
8. 2022 High

   Extended CFB beyond opsonization by placing it upstream of C3 in a signaling cascade driving ceramide biosynthesis and tubular injury.

   Evidence Cfb knockout mice, HK-2 siRNA knockdown, C3 knockdown epistasis, and pharmacological/ceramide rescue under high-glucose conditions

   PMID:36546481

   Open questions at the time

   • Mechanism by which CFB activates NF-κB upstream of C3 in tubular cells not resolved
   • Whether convertase activity is required for the signaling role not tested
9. 2023 High

   Defined how a human CFB SNP impairs function, showing G252S creates a glycosylation site that reduces C3b binding, cleavage, and complement-driven phagocytosis.

   Evidence Site-directed mutagenesis, cell-free C3b binding/cleavage assays, macrophage phagocytosis flow cytometry, and patient serum assays

   PMID:37080587

   Open questions at the time

   • Structural basis of how the de novo glycan blocks C3b binding not resolved
   • In vivo consequences in Crohn's disease not directly demonstrated

• How CFB's convertase activity relates mechanistically to its C3-dependent NF-κB/ceramide signaling role, and whether disease variants act through one or both functions, remains unresolved.
• No structural model linking variant sites to function
• Receptor/effector coupling CFB to intracellular NF-κB signaling unknown