C3a (complement)

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The classical and alternative complement pathways. Complement pathway.svg
The classical and alternative complement pathways.

C3a is one of the proteins formed by the cleavage of complement component 3; the other is C3b. C3a is a 77 residue anaphylatoxin that binds to the C3a receptor (C3aR), a class A G protein-coupled receptor. It plays a large role in the immune response.

Contents

C3a molecules induce responses through the GPCR C3a receptor. Like other anaphylatoxins, C3a is regulated by cleavage of its carboxy-terminal arginine, which results in a molecule with lowered inflammatory function (C3a desarginine). [1]

C3a is an effector of the complement system with a range of functions including T cell activation and survival, [2] angiogenesis stimulation, [3] chemotaxis, mast cell degranulation, [4] and macrophage activation. [5] It has been shown to have both proinflammatory and anti-inflammatory responses, its activity able to counteract the proinflammatory effects of C5a. [6]

Initial research in mice demonstrating an effective treatment after stroke is leading to further investigation to determine whether application to humans has potential. [7]

Structure

C3a

C3a is a strongly basic and highly cationic 77 residue protein with a molecular mass of approximately 10 kDa. [8] Residues 17-66 are made up of three anti-parallel helices and three disulfide bonds, which confer stability to the protein. The N-terminus consists of a fourth flexible helical structure, while the C terminus is disordered. [9] C3a has a regulatory process and a structure homologous to complement component C5a, with which it shares 36% of its sequence identity. [1]

Receptor

C3a induces an immunological response through a 482 residue G-protein-coupled receptor called C3a receptor (C3aR). The C3aR is similarly structurally homologous to C5aR, but contains an extracellular domain with more than 160 amino acids. [10] Specific binding sites for interactions between C3a and C3aR are unknown, but it has been shown that sulfation of tyrosine 174, one of the amino acids in the extracellular domain, is required for C3a binding. [11] It has also been demonstrated that the C3aR N terminus is not required for ligand binding. [12]

Formation

C3a formation occurs through activation and cleavage of complement component 3 in a reaction catalyzed by C3-convertase. There are three pathways of activation, each of which leads to the formation of C3a and C3b, which is involved in antigen opsonization. Other than the alternative pathway, which is constantly active, C3a formation is triggered by pathogenic infection.

Classical pathway

The classical pathway of complement activation is initiated when the C1 complex, made up of C1r and C1s serine proteases, recognizes the Fc region of IgM or IgG antibodies bound to a pathogen. C1q mediates the classical pathway by activating the C1 complex, which cleaves C4 and C2 into smaller fragments (C4a, C4b, C2a, and C2b). C4a and C2b form C4bC2b, also known as C3 convertase. [13]

Lectin pathway

The lectin pathway is activated when pattern-recognition receptors, like mannan-binding lectin or ficolins, recognize and bind to pathogen-associated molecular patterns on the antigen, including sugars. [14] These bound receptors then complex with Mannose-Binding Lectin-Associated Serine Proteases (MASPs), which have proteolytic activity similar to the C1 complex. The MASPs cleave C4 and C2, resulting in C3 convertase formation. [15]

Alternative pathway

The alternative pathway of complement activation is typically always active at low levels in blood plasma through a process called tick-over, in which C3 spontaneously hydrolyzes into its active form, C3(H2O). This activation induces a conformational change in the thioester domain of C3(H2O) that allows it to bind to a plasma protein called Factor B. This complex is then cleaved by Factor D, a serine protease, to form C3b(H2O)Bb, or fluid-phase C3-convertase. This complex has the ability to catalyze the formation of C3a and C3b after it binds properdin, a globulin protein, and is stabilized. [16]

Functions

Anaphylatoxins are small complement peptides that induce proinflammatory responses in tissues. C3a is primarily regarded for its role in the innate and adaptive immune responses as an anaphylatoxin, moderating and activating multiple inflammatory pathways.

Role in innate immunity

The roles of C3a in innate immunity, upon binding C3aR, include increased vasodilation via endothelial cell contraction, increased vascular permeability, and mast cell and basophil degranulation of histamine, induction of respiratory burst and subsequent degradation of pathogens by neutrophils, macrophages, and eosinophils, and regulation of cationic eosinophil protein migration, adhesion, and production. [17] C3a is also able to play a role in chemotaxis for mast cells and eosinophils, but C5a is a more potent chemoattractant. [18]

Traditionally thought to serve a strictly pro-inflammatory role, recent investigations have shown that C3a can also work against C5a to serve an anti-inflammatory role. In addition, migration and degranulation of neutrophils can be suppressed in the presence of C3a. [6]

Role in adaptive immunity

C3a also plays an important role in adaptive immunity, moderating leukocyte production and proliferation. C3a is able to regulate B cell and monocyte production of IL-6 and TNF-α, and human C3a has been shown to dampen the polyclonal immune response through dose-dependent regulation of B cell molecule production. [19] C3aR signaling along antigen-presenting cells' CD28 and CD40L pathways also plays a role in T cell proliferation and differentiation. [2] C3aR has been shown to be necessary for TH1 cell generation and regulates TH1 IL-10 expression, while an absence of active C3aR on dendritic cells upregulates regulatory T cell production. The absence of C3 has also been shown to decrease IL-2 receptor expression on T cells. [19]

Regulation

Regulation of complement activation

Levels of complement are regulated by moderating convertase formation and enzymatic activity. C3 convertase formation is primarily regulated by levels of active C3b and C4b. Factor I, a serine protease activated by cofactors, can cleave and C3b and C4b, thus preventing convertase formation. C3 convertase activity is also regulated without C3b inactivation, through complement control proteins, including decay-accelerating factors that function to speed up C3 convertase half-lives and avert convertase formation. [14]

Deactivation

C3a, like other anaphylatoxins, has a C-terminal arginine residue. Serum carboxypeptidase B, a protease, cleaves the arginine residue from C3a, forming the desArg derivative of C3a, also known as acylation stimulating protein (ASP). Unlike C5a desArg, this version of C3a has no proinflammatory activity. [1] However, ASP functions as a hormone in the adipose tissue, moderating fatty acid migration to adipocytes and triacylglycerol synthesis. [20] In addition, it has been shown that ASP downregulates the polyclonal immune response in the same way C3a does. [14]

Related Research Articles

<span class="mw-page-title-main">Complement system</span> Part of the immune system that enhances the ability of antibodies and phagocytic cells

The complement system, also known as complement cascade, is a part of the immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells from an organism, promote inflammation, and attack the pathogen's cell membrane. It is part of the innate immune system, which is not adaptable and does not change during an individual's lifetime. The complement system can, however, be recruited and brought into action by antibodies generated by the adaptive immune system.

<span class="mw-page-title-main">Classical complement pathway</span> Aspect of the immune system

The classical complement pathway is one of three pathways which activate the complement system, which is part of the immune system. The classical complement pathway is initiated by antigen-antibody complexes with the antibody isotypes IgG and IgM.

<span class="mw-page-title-main">Alternative complement pathway</span> Type of cascade reaction of the complement system

The alternative pathway is a type of cascade reaction of the complement system and is a component of the innate immune system, a natural defense against infections.

<span class="mw-page-title-main">C3-convertase</span>

C3 convertase belongs to family of serine proteases and is necessary in innate immunity as a part of the complement system which eventuate in opsonisation of particles, release of inflammatory peptides, C5 convertase formation and cell lysis.

<span class="mw-page-title-main">Complement receptor 1</span> Mammalian protein found in Homo sapiens

Complement receptor type 1 (CR1) also known as C3b/C4b receptor or CD35 is a protein that in humans is encoded by the CR1 gene.

<span class="mw-page-title-main">Anaphylatoxin</span>

Anaphylatoxins, or complement peptides, are fragments that are produced as part of the activation of the complement system. Complement components C3, C4 and C5 are large glycoproteins that have important functions in the immune response and host defense. They have a wide variety of biological activities and are proteolytically activated by cleavage at a specific site, forming a- and b-fragments. A-fragments form distinct structural domains of approximately 76 amino acids, coded for by a single exon within the complement protein gene. The C3a, C4a and C5a components are referred to as anaphylatoxins: they cause smooth muscle contraction, vasodilation, histamine release from mast cells, and enhanced vascular permeability. They also mediate chemotaxis, inflammation, and generation of cytotoxic oxygen radicals. The proteins are highly hydrophilic, with a mainly alpha-helical structure held together by 3 disulfide bridges.

Opsonins are extracellular proteins that, when bound to substances or cells, induce phagocytes to phagocytose the substances or cells with the opsonins bound. Thus, opsonins act as tags to label things in the body that should be phagocytosed by phagocytes. Different types of things ("targets") can be tagged by opsonins for phagocytosis, including: pathogens, cancer cells, aged cells, dead or dying cells, excess synapses, or protein aggregates. Opsonins help clear pathogens, as well as dead, dying and diseased cells.

<span class="mw-page-title-main">Complement component 3</span> Protein-coding gene in the species Homo sapiens

Complement component 3, often simply called C3, is a protein of the immune system that is found primarily in the blood. It plays a central role in the complement system of vertebrate animals and contributes to innate immunity. In humans it is encoded on chromosome 19 by a gene called C3.

<span class="mw-page-title-main">C5-convertase</span> Serine protease that plays key role in innate immunity.

C5 convertase is an enzyme belonging to a family of serine proteases that play key role in the innate immunity. It participates in the complement system ending with cell death.

<span class="mw-page-title-main">Complement component 5a</span> Protein fragment

C5a is a protein fragment released from cleavage of complement component C5 by protease C5-convertase into C5a and C5b fragments. C5b is important in late events of the complement cascade, an orderly series of reactions which coordinates several basic defense mechanisms, including formation of the membrane attack complex (MAC), one of the most basic weapons of the innate immune system, formed as an automatic response to intrusions from foreign particles and microbial invaders. It essentially pokes microscopic pinholes in these foreign objects, causing loss of water and sometimes death. C5a, the other cleavage product of C5, acts as a highly inflammatory peptide, encouraging complement activation, formation of the MAC, attraction of innate immune cells, and histamine release involved in allergic responses. The origin of C5 is in the hepatocyte, but its synthesis can also be found in macrophages, where it may cause local increase of C5a. C5a is a chemotactic agent and an anaphylatoxin; it is essential in the innate immunity but it is also linked with the adaptive immunity. The increased production of C5a is connected with a number of inflammatory diseases.

<span class="mw-page-title-main">Properdin</span> Protein-coding gene in the species Homo sapiens

Properdin is a protein that in humans is encoded by the CFP gene.

<span class="mw-page-title-main">Lectin pathway</span>

The lectin pathway or MBL pathway is a type of cascade reaction in the complement system, similar in structure to the classical complement pathway, in that, after activation, it proceeds through the action of C4 and C2 to produce activated complement proteins further down the cascade. In contrast to the classical complement pathway, the lectin pathway does not recognize an antibody bound to its target. The lectin pathway starts with mannose-binding lectin (MBL) or ficolin binding to certain sugars.

<span class="mw-page-title-main">MASP1 (protein)</span> Protein-coding gene in the species Homo sapiens

Mannan-binding lectin serine protease 1 also known as mannose-associated serine protease 1 (MASP-1) is an enzyme that in humans is encoded by the MASP1 gene.

<span class="mw-page-title-main">Decay-accelerating factor</span> Mammalian protein found in Homo sapiens

Complement decay-accelerating factor, also known as CD55 or DAF, is a protein that, in humans, is encoded by the CD55 gene.

<span class="mw-page-title-main">C3a receptor</span> Protein-coding gene in humans

The C3a receptor also known as complement component 3a receptor 1 (C3AR1) is a G protein-coupled receptor protein involved in the complement system.

<span class="mw-page-title-main">C3b</span>

C3b is the larger of two elements formed by the cleavage of complement component 3, and is considered an important part of the innate immune system. C3b is potent in opsonization: tagging pathogens, immune complexes (antigen-antibody), and apoptotic cells for phagocytosis. Additionally, C3b plays a role in forming a C3 convertase when bound to Factor B, or a C5 convertase when bound to C4b and C2b or when an additional C3b molecule binds to the C3bBb complex.

<span class="mw-page-title-main">C5a receptor</span> Mammalian protein found in Homo sapiens

The C5a receptor also known as complement component 5a receptor 1 (C5AR1) or CD88 is a G protein-coupled receptor for C5a. It functions as a complement receptor. C5a receptor 1 modulates inflammatory responses, obesity, development and cancers. From a signaling transduction perspective, C5a receptor 1 activation is implicated in β-arrestin2 recruitment via Rab5a, coupling of Gαi proteins, ERK1/2 phosphorylation, calcium mobilization and Rho activation leading to downstream functions, such as secretion of cytokines, chemotaxis, and phagocytosis.

The following outline is provided as an overview of and topical guide to immunology:

Complement 3 deficiency is a genetic condition affecting complement component 3 (C3). People can suffer from either primary or secondary C3 deficiency. Primary C3 deficiency refers to an inherited autosomal-recessive disorder that involves mutations in the gene for C3. Secondary C3 deficiency results from a lack of factor I or factor H, two proteins that are key for the regulation of C3. Both primary and secondary C3 deficiency are characterized by low levels or absence of C3.

Passive antibody therapy, also called serum therapy, is a subtype of passive immunotherapy that administers antibodies to target and kill pathogens or cancer cells. It is designed to draw support from foreign antibodies that are donated from a person, extracted from animals, or made in the laboratory to elicit an immune response instead of relying on the innate immune system to fight disease. It has a long history from the 18th century for treating infectious diseases and is now a common cancer treatment. The mechanism of actions include: antagonistic and agonistic reaction, complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC).

References

  1. 1 2 3 Bajic, Goran; Yatime, Laure; Klos, Andreas; Andersen, Gregers Rom (2013-02-01). "Human C3a and C3a desArg anaphylatoxins have conserved structures, in contrast to C5a and C5a desArg". Protein Science. 22 (2): 204–212. doi:10.1002/pro.2200. ISSN   1469-896X. PMC   3588916 . PMID   23184394.
  2. 1 2 Strainic, MG; Liu, J; Huang, D; An, F; Lalli, PN; Muqim, N; Shapiro, VS; Dubyak, GR; Heeger, PS; Medof, ME (March 2008). "Locally produced complement fragments C5a and C3a provide both costimulatory and survival signals to naive CD4+ T cells". Immunity. 28 (3): 425–35. doi:10.1016/j.immuni.2008.02.001. PMC   2646383 . PMID   18328742.
  3. ↑ Khan, MA; Assiri, AM; Broering, DC (22 July 2015). "Complement and macrophage crosstalk during process of angiogenesis in tumor progression". Journal of Biomedical Science. 22 (1): 58. doi: 10.1186/s12929-015-0151-1 . PMC   4511526 . PMID   26198107.
  4. ↑ Reid, Robert C.; Yau, Mei-Kwan; Singh, Ranee; Hamidon, Johan K.; Reed, Anthony N.; Chu, Peifei; Suen, Jacky Y.; Stoermer, Martin J.; Blakeney, Jade S.; Lim, Junxian; Faber, Jonathan M.; Fairlie, David P. (21 November 2013). "Downsizing a human inflammatory protein to a small molecule with equal potency and functionality". Nature Communications. 4 (1): 2802. Bibcode:2013NatCo...4.2802R. doi: 10.1038/ncomms3802 . ISSN   2041-1723. PMID   24257095. S2CID   5465825.
  5. ↑ Mathern, DR; Heeger, PS (4 September 2015). "Molecules Great and Small: The Complement System". Clinical Journal of the American Society of Nephrology. 10 (9): 1636–50. doi:10.2215/cjn.06230614. PMC   4559511 . PMID   25568220.
  6. 1 2 Coulthard, LG; Woodruff, TM (15 April 2015). "Is the complement activation product C3a a proinflammatory molecule? Re-evaluating the evidence and the myth". Journal of Immunology. 194 (8): 3542–8. doi: 10.4049/jimmunol.1403068 . PMID   25848071.
  7. ↑ Anna Stokowska, Markus Aswendt, Daniel Zucha, Stephanie Lohmann, Frederique Wieters, Javier Morán Suarez, Alison L. Atkins, YiXian Li, Maria Miteva, Julia Lewin, Dirk Wiedermann, Michael Diedenhofen, Åsa Torinsson Naluai, Pavel Abaffy, Lukas Valihrach, Mikael Kubista, Mathias Hoehn, Milos Pekny, and Marcela Pekna, Complement C3a treatment accelerates recovery after stroke via modulation of astrocyte reactivity and cortical connectivity , Journal of Clinical Investigation, March 30, 2023
  8. ↑ Zhou, Wuding (2012-02-01). "The new face of anaphylatoxins in immune regulation". Immunobiology. 217 (2): 225–234. doi:10.1016/j.imbio.2011.07.016. ISSN   1878-3279. PMID   21856033.
  9. ↑ Chang, Jui-Yoa; Lin, Curtis C. -J.; Salamanca, Silvia; Pangburn, Michael K.; Wetsel, Rick A. (2008-12-15). "Denaturation and unfolding of human anaphylatoxin C3a: An unusually low covalent stability of its native disulfide bonds". Archives of Biochemistry and Biophysics. 480 (2): 104–110. doi:10.1016/j.abb.2008.09.013. PMC   2636726 . PMID   18854167.
  10. ↑ Ames, R. S.; Li, Y.; Sarau, H. M.; Nuthulaganti, P.; Foley, J. J.; Ellis, C.; Zeng, Z.; Su, K.; Jurewicz, A. J. (1996-08-23). "Molecular cloning and characterization of the human anaphylatoxin C3a receptor". The Journal of Biological Chemistry. 271 (34): 20231–20234. doi: 10.1074/jbc.271.34.20231 . ISSN   0021-9258. PMID   8702752.
  11. ↑ Gao, Jinming; Choe, Hyeryun; Bota, Dalena; Wright, Paulette L.; Gerard, Craig; Gerard, Norma P. (2003-09-26). "Sulfation of tyrosine 174 in the human C3a receptor is essential for binding of C3a anaphylatoxin". The Journal of Biological Chemistry. 278 (39): 37902–37908. doi: 10.1074/jbc.M306061200 . ISSN   0021-9258. PMID   12871936.
  12. ↑ Crass, T.; Ames, R. S.; Sarau, H. M.; Tornetta, M. A.; Foley, J. J.; Köhl, J.; Klos, A.; Bautsch, W. (1999-03-26). "Chimeric receptors of the human C3a receptor and C5a receptor (CD88)". The Journal of Biological Chemistry. 274 (13): 8367–8370. doi: 10.1074/jbc.274.13.8367 . ISSN   0021-9258. PMID   10085065.
  13. ↑ Arlaud, G. J.; Gaboriaud, C.; Thielens, N. M.; Rossi, V.; Bersch, B.; Hernandez, J. F.; Fontecilla-Camps, J. C. (2001-04-01). "Structural biology of C1: dissection of a complex molecular machinery". Immunological Reviews. 180: 136–145. doi:10.1034/j.1600-065x.2001.1800112.x. ISSN   0105-2896. PMID   11414355. S2CID   21136630.
  14. 1 2 3 Dunkelberger, Jason R.; Song, Wen-Chao (2010-01-01). "Complement and its role in innate and adaptive immune responses". Cell Research. 20 (1): 34–50. doi: 10.1038/cr.2009.139 . ISSN   1748-7838. PMID   20010915.
  15. ↑ Degn, Søren E.; Thiel, Steffen; Jensenius, Jens C. (2007-01-01). "New perspectives on mannan-binding lectin-mediated complement activation". Immunobiology. 212 (4–5): 301–311. doi:10.1016/j.imbio.2006.12.004. ISSN   0171-2985. PMID   17544815.
  16. ↑ Merle, Nicolas S.; Church, Sarah Elizabeth; Fremeaux-Bacchi, Veronique; Roumenina, Lubka T. (2015-01-01). "Complement System Part I - Molecular Mechanisms of Activation and Regulation". Frontiers in Immunology. 6: 262. doi: 10.3389/fimmu.2015.00262 . ISSN   1664-3224. PMC   4451739 . PMID   26082779.
  17. ↑ Klos, Andreas; Tenner, Andrea J.; Johswich, Kay-Ole; Ager, Rahasson R.; Reis, Edimara S.; Köhl, Jörg (2009-09-01). "The role of the anaphylatoxins in health and disease". Molecular Immunology. 12th European Meeting on Complement in Human Disease12th European Meeting on CHD12th European Meeting on Complement in Human Disease. 46 (14): 2753–2766. doi:10.1016/j.molimm.2009.04.027. PMC   2725201 . PMID   19477527.
  18. ↑ Schraufstatter, Ingrid U.; DiScipio, Richard G.; Zhao, Ming; Khaldoyanidi, Sophia K. (2009-03-15). "C3a and C5a Are Chemotactic Factors for Human Mesenchymal Stem Cells, Which Cause Prolonged ERK1/2 Phosphorylation". The Journal of Immunology. 182 (6): 3827–3836. doi: 10.4049/jimmunol.0803055 . ISSN   0022-1767. PMID   19265162.
  19. 1 2 Merle, Nicolas S.; Noe, Remi; Halbwachs-Mecarelli, Lise; Fremeaux-Bacchi, Veronique; Roumenina, Lubka T. (2015-05-26). "Complement System Part II: Role in Immunity". Frontiers in Immunology. 6: 257. doi: 10.3389/fimmu.2015.00257 . ISSN   1664-3224. PMC   4443744 . PMID   26074922.
  20. ↑ Barbu, Andreea; Hamad, Osama A.; Lind, Lars; Ekdahl, Kristina N.; Nilsson, Bo (2015-09-01). "The role of complement factor C3 in lipid metabolism". Molecular Immunology. 15th European Meeting on Complement in Human Disease 2015, Uppsala, Sweden. 67 (1): 101–107. doi:10.1016/j.molimm.2015.02.027. PMID   25746915.
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