C9

What is C9 protein?

C9 (complement C9) gene is a protein coding gene which situated on the short arm of chromosome 5 at locus 5p13. C9 is A multidomain protein containing the N-terminal type 1 thromboplaque protein (TSP) domain, LDL-receptor class A repeats, and multiple potential transmembrane regions. C9) is a key component of the human complement system, which plays a crucial role in the formation of the Membrane Attack Complex (MAC), which forms pores by combining with other components of the MAC. This allows MAC to effectively penetrate and destroy the cell membrane of the target cell. During complement activation, multiple copies of the C9 molecule are inserted into the MAC, forming a polyC9 structure that is key to the perforation activity of the MAC. The C9 protein is consisted of 559 amino acids and its molecular mass is approximately 63.2 kDa.

What is the function of C9 protein?

C9 is the final component of the complement system's membrane attack complex, which combines with other components of the MAC to complete the formation of pores, resulting in the cleavage of bacteria or target cells. The assembly of MAC on the bacterial membrane forms a hole, thereby destroying the bacterial membrane tissue, which is the primary biological function of C9.

C9 plays a vital immune defense role against invading microorganisms, such as bacteria and viruses, by participating in the formation of MAC. C9 and its related complement activation pathways play an important role in the regulation of immune response, including enhancing antibody response, clearing immune complexes and apoptotic cells.

C9 Related Signaling Pathway

C9 protein is mainly involved in three signaling pathways in the complement system: classical complement pathway, replacement complement pathway and lectin pathway. Specifically, the classical complement pathway is an antibody-mediated process of complement activation in which C9, as the last component of the membrane attack complex (MAC), binds to the C5b-8 complex to form a channel capable of penetrating the cell membrane, resulting in the cleavage of the target cell.

Alternative complement pathway: Also known as the bypass pathway, it does not rely on antibodies, but directly activates C3 through complement proteins such as B factors, D factors, and readiness hormone (P-factor), which in turn triggers a cascade of reactions. C9 plays the same role in this pathway as the classical pathway, participating in the formation of MAC and carrying out the cell lysis function.

The lectin pathway directly recognizes the sugar structure on the surface of pathogens through pattern recognition molecules such as mannose-binding lectin (MBL), thereby activating the complement system. C9's role in this pathway is also as part of the MAC, involved in the elimination of foreign pathogens.

C9 Related Diseases

Diseases associated with the C9 protein include inherited complement deficiency disorders and autoimmune disorders. Hereditary complement deficiency diseases are caused by the abnormal function of the C9 protein due to mutations in the C9 gene. The most common hereditary complement deficiency disorder is hereditary glomerulonephritis, which is characterized by recurrent episodes of hematuria and proteinuria that can eventually lead to kidney failure. Other hereditary complement deficiency diseases include hereditary angioedema and hereditary IgA nephropathy.

Autoimmune diseases are diseases in which the immune system attacks its own tissues. In some autoimmune diseases, C9 protein may be involved in pathological processes. For example, in rheumatoid arthritis, the C9 protein may be involved in the formation and deposition of immune complexes that lead to arthritis symptoms. In addition, other autoimmune diseases such as systemic lupus erythematosus may also be associated with abnormal function of the C9 protein.

Bioapplications of C9

C9 protein is used as a laboratory reagent for the detection of complement activity and the functional study of complement system. In clinical diagnosis, the detection of C9 protein can help diagnose certain complement-related diseases, such as hereditary complement deficiency. The activity and expression level of C9 protein can be used as an indicator to evaluate the effectiveness of therapeutic strategies, especially in the treatment of diseases related to the complement system.

Case Study 1: Mariann Kremlitzka, 2018

Age-related macular degeneration (AMD) is a progressive disease of the central retina and the leading cause of irreversible vision loss in the western world. The involvement of abnormal complement activation in AMD has been suggested by association of variants in genes encoding complement proteins with disease development. A low-frequency variant (p.P167S) in the complement component C9 (C9) gene was recently shown to be highly associated with AMD; however, its functional outcome remains largely unexplored. This study revealed five novel rare genetic variants (p.M45L, p.F62S, p.G126R, p.T170I and p.A529T) in C9 in AMD patients, and evaluate their functional effects in vitro together with the previously identified (p.R118W and p.P167S) C9 variants. The results demonstrate that the concentration of C9 is significantly elevated in patients' sera carrying the p.M45L, p.F62S, p.P167S and p.A529T variants compared with non-carrier controls. Comparing the polymerization of the C9 variants, the p.P167S mutant spontaneously aggregates, while the other mutant proteins (except for C9 p.A529T) fail to polymerize in the presence of zinc.

Fig1. Measurement of serum C9 levels in C9 carriers.

Fig2. Concentration of C9 in the secreted supernatants was measured by ELISA.

Case Study 2: Hangeun Kim, 2013

Hepatitis C virus (HCV) proteins inhibit complement component expression, which may attenuate immunity against infection. This study examined whether HCV regulates the membrane attack complex (MAC) via complement component C9. MAC is composed of C5b to C9 (C5b-9) and mediates cell lysis of invaded pathogens. Liver biopsy specimens from chronically HCV-infected patients exhibited a lower level of C9 mRNA expression than liver biopsy specimens from unrelated disease or healthy control human liver RNA. Hepatocytes infected with cell culture-grown HCV or expressing HCV core protein also displayed significant repression of C9 mRNA and protein levels. Promoter analysis suggested that the T cell factor-4 (TCF-4E) transcription factor is responsible for HCV core-mediated C9 promoter regulation. Sera from chronically HCV-infected patients displayed a lower level of C5b-9 and a reduced antimicrobial effect on model organisms compared to unrelated patient sera or sera from healthy volunteers.

Fig3. The repression of C9 protein was examined with HCV genotype 2a-infected or uninfected hepatocyte lysates by Western blotting.

Fig4. IFN-γ-mediated dose-dependent stimulation of C9 promoter activity is shown after 18 h of treatment.

C9 has several biochemical functions, for example, . Some of the functions are cooperated with other proteins, some of the functions could acted by C9 itself. We selected most functions C9 had, and list some proteins which have the same functions with C9. You can find most of the proteins on our site.

C9 has direct interactions with proteins and molecules. Those interactions were detected by several methods such as yeast two hybrid, co-IP, pull-down and so on. We selected proteins and molecules interacted with C9 here. Most of them are supplied by our site. Hope this information will be useful for your research of C9.

d-mannose