C4bp, short for C4b-binding protein, is a key regulator of the complement system. It plays a crucial role in preventing excessive complement activation, thus maintaining immune homeostasis. It is also involved in the anticoagulant protein C pathway as it can bind to anticoagulant protein S, regulating its cofactor activity [4].

Screening of Neisseria gonorrhoeae strains showed that C4bp binding to the porin of the bacteria contributes to serum resistance. C4bp bound to gonococci retains its cofactor (C4b-degrading) function. Different regions of the Por molecule, like loop 1 of Por1A and loops 5 and 7 of Por1B, are required for C4bp binding. The binding nature varies; C4bp-Por1B is ionic while C4bp-Por1A is hydrophobic. Inhibiting C4bp binding can lead to the killing of otherwise serum-resistant strains [1]. Designing chimeric proteins like C4BP-IgM can enhance complement activation and killing of gonococci, potentially serving as an adjunct to conventional antimicrobials for treating gonorrhea [2,8]. In Streptococcus pyogenes, antigenically variable M proteins recruit C4bp to the bacterial surface to evade the immune system, and specific C4bp-binding sequence patterns in M and Enn proteins have been identified, which could be used in vaccine immunogen design [6,7]. Also, the minor isoform C4BP(β-) has anti-inflammatory and immunomodulatory effects, which can attenuate inflammation in DSS-induced murine colitis and in myeloid cells from IBD patients, and a recombinant analogue PRP6-HO7 with only immunomodulatory activity has a similar outcome [3,5].

In conclusion, C4bp is essential for complement regulation and has implications in anticoagulation. Its role in bacterial immune evasion and potential as a therapeutic target in treating infections like gonorrhea is significant. The anti-inflammatory and immunomodulatory functions of its isoform C4BP(β-) suggest its potential in treating inflammatory bowel diseases. Research on C4bp using models helps understand its diverse biological functions and its importance in disease-related processes.

References:

1. Ram, S, Cullinane, M, Blom, A M, Dahlbäck, B, Rice, P A. . C4bp binding to porin mediates stable serum resistance of Neisseria gonorrhoeae. In International immunopharmacology, 1, 423-32. doi:. https://pubmed.ncbi.nlm.nih.gov/11367527/

2. Bettoni, Serena, Shaughnessy, Jutamas, Maziarz, Karolina, Ram, Sanjay, Blom, Anna M. 2019. C4BP-IgM protein as a therapeutic approach to treat Neisseria gonorrhoeae infections. In JCI insight, 4, . doi:10.1172/jci.insight.131886. https://pubmed.ncbi.nlm.nih.gov/31661468/

3. Serrano, Inmaculada, Luque, Ana, Ruiz-Cerulla, Alexandra, Guardiola, Jordi, Aran, Josep M. 2023. C4BP(β-)-mediated immunomodulation attenuates inflammation in DSS-induced murine colitis and in myeloid cells from IBD patients. In Pharmacological research, 197, 106948. doi:10.1016/j.phrs.2023.106948. https://pubmed.ncbi.nlm.nih.gov/37806602/

4. van de Poel, R H, Meijers, J C, Bouma, B N. . The interaction between anticoagulant protein S and complement regulatory C4b-binding protein (C4BP). In Trends in cardiovascular medicine, 10, 71-6. doi:. https://pubmed.ncbi.nlm.nih.gov/11150733/

5. Serrano, Inmaculada, Luque, Ana, Mitjavila, Francesca, Torras, Joan, Aran, Josep M. 2022. The Hidden Side of Complement Regulator C4BP: Dissection and Evaluation of Its Immunomodulatory Activity. In Frontiers in immunology, 13, 883743. doi:10.3389/fimmu.2022.883743. https://pubmed.ncbi.nlm.nih.gov/35547734/

6. Kolesiński, Piotr, McGowan, Matthew, Botteaux, Anne, Smeesters, Pierre R, Ghosh, Partho. 2024. Conservation of C4BP-binding sequence patterns in Streptococcus pyogenes M and Enn proteins. In The Journal of biological chemistry, 300, 107478. doi:10.1016/j.jbc.2024.107478. https://pubmed.ncbi.nlm.nih.gov/38879009/

7. Kolesiński, Piotr, McGowan, Matthew, Botteaux, Anne, Smeesters, Pierre R, Ghosh, Partho. 2024. Conservation of C4BP-binding Sequence Patterns in Streptococcus pyogenes M and Enn Proteins. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.04.22.590534. https://pubmed.ncbi.nlm.nih.gov/38712057/

8. Bettoni, Serena, Maziarz, Karolina, Stone, M Rhia L, Ram, Sanjay, Blom, Anna M. 2021. Serum Complement Activation by C4BP-IgM Fusion Protein Can Restore Susceptibility to Antibiotics in Neisseria gonorrhoeae. In Frontiers in immunology, 12, 726801. doi:10.3389/fimmu.2021.726801. https://pubmed.ncbi.nlm.nih.gov/34539665/