S100 calcium-binding protein A9 (S100A9) also known as migration inhibitory factor-related protein 14 (MRP14) or calgranulin B is a protein that in humans is encoded by the S100A9 gene. [5]
The proteins S100A8 and S100A9 form a heterodimer called calprotectin.
S100A9 is a member of the S100 family of proteins containing 2 EF hand calcium-binding motifs. S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. S100 genes include at least 13 members which are located as a cluster on chromosome 1q21. This protein may function in the inhibition of casein kinase. [5]
MRP14 complexes with MRP-8 (S100A8), another member of the S100 family of calcium-modulated proteins; together, MRP8 and MRP14 regulate myeloid cell function by binding to Toll-like receptor 4 (TLR4) [6] [7] and the receptor for advanced glycation end products. [8]
Intracellular S100A9 alters mitochondrial homeostasis within neutrophils. As a result, neutrophils lacking S100A9 produce higher levels of mitochondrial superoxide and undergo elevated levels of suicidal NETosis in response to bacterial pathogens. [9] Furthermore, S100A9-deficient mice are protected from systemic Staphylococcus aureus infections with lower bacterial burdens in the heart, which suggests an organ-specific function for S100A9. [9] [10]
Altered expression of the S100A9 protein is associated with the disease cystic fibrosis. [5]
MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury by promoting leukocyte recruitment. [11]
MRP-8/14 also regulates vascular insults by controlling neutrophil and macrophage accumulation, macrophage cytokine production, and SMC proliferation. The above study has shown therefore the deficiency of MRP-8 and MRP-14 reduces neutrophil- and monocyte-dependent vascular inflammation and attenuates the severity of diverse vascular injury responses in vivo. MRP-8/14 may be a useful biomarker of platelet and inflammatory disease activity in atherothrombosis and may serve as a novel target for therapeutic intervention. [12] Also, the platelet transcriptome reveals quantitative differences between acute and stable coronary artery disease. MRP-14 expression increases before ST-segment-elevation myocardial infarction, (STEMI), and increasing plasma concentrations of MRP-8/14 among healthy individuals predict the risk of future cardiovascular events. [13]
S100A9 (myeloid-related protein 14, MRP 14 or calgranulin B) has been implicated in the abnormal differentiation of myeloid cells in the stroma of cancer, and to leukemia progression. [14] [15] This contributes to creating an overall immunosuppressive microenvironment that may contribute to the inability of a protective or therapeutic cellular immune response to be generated by the tumor-bearing host. Outside of malignancy, S100A9 in association with its dimerization partner, S100A8 (MRP8 or calgranulin A) signals for lymphocyte recruitment in sites of inflammation. [16] S100A9/A8 (synonyma: Calgranulin A/B; Calprotectin) are also regarded as marker proteins for a number of inflammatory diseases in humans, especially in rheumatoid arthritis and inflammatory bowel disease (IBD).
Myeloid-related protein (MRP)-8 is an inflammatory protein found in several mucosal secretions. In cervico-vaginal secretions MRP-8 can stimulate HIV production; [17] and thus might be involved in sexual transmission of HIV, as well as other sexually transmitted diseases (STD). In Vitro studies have shown that HIV-inducing of recombinant MRP-8 can increase HIV expression by up to 40-fold. [17]
A S100A9 knockout mouse has (a mouse mutant, that is deficient of S100A9) been constructed. This mouse is fertile, viable and healthy. However, expression of S100A8 protein, the dimerization partner of S100A9, is also absent in these mice in differentiated myeloid cells. [18] This mouse line has been used to study the role of S100A9 and S100A8 in a number of experimental inflammatory conditions.
Annexin is a common name for a group of cellular proteins. They are mostly found in eukaryotic organisms.
The S100 proteins are a family of low molecular-weight proteins found in vertebrates characterized by two calcium-binding sites that have helix-loop-helix ("EF-hand-type") conformation. At least 21 different S100 proteins are known. They are encoded by a family of genes whose symbols use the S100 prefix, for example, S100A1, S100A2, S100A3. They are also considered as damage-associated molecular pattern molecules (DAMPs), and knockdown of aryl hydrocarbon receptor downregulates the expression of S100 proteins in THP-1 cells.
Calgranulin is an S100 calcium-binding protein that is expressed in multiple cell types, including renal epithelial cells and neutrophils.
C-X-C motif chemokine 5 is a protein that in humans is encoded by the CXCL5 gene.
Protein S100-A4 (S100A4) is a protein that in humans is encoded by the S100A4 gene.
S100 calcium-binding protein A2 (S100A2) is a protein that in humans is encoded by the S100A2 gene and it is located on chromosome 1q21 with other S100 proteins.
S100 calcium-binding protein B (S100B) is a protein of the S-100 protein family.
S100 calcium-binding protein A8 (S100A8) is a protein that in humans is encoded by the S100A8 gene. It is also known as calgranulin A.
S100 calcium-binding protein A6 (S100A6) is a protein that in humans is encoded by the S100A6 gene.
S100 calcium-binding protein A12 (S100A12) is a protein that in humans is encoded by the S100A12 gene. Human S100A12, also known as calgranulin C, was first described in 1995.
S100 calcium-binding protein P (S100P) is a protein that in humans is encoded by the S100P gene.
ATP-binding cassette transporter sub-family C member 11, also MRP8, is a membrane transporter that exports certain molecules from inside a cell. It is a protein that in humans is encoded by gene ABCC11.
Serine/threonine-protein kinase 38 is an enzyme that in humans is encoded by the STK38 gene.
ATP-binding cassette sub-family A member 3 is a protein that in humans is encoded by the ABCA3 gene.
Grancalcin is a protein that in humans is encoded by the GCA gene.
Death-associated protein kinase 2 is an enzyme that in humans is encoded by the DAPK2 gene.
S100 calcium-binding protein A5 (S100A5) is a protein that in humans is encoded by the S100A5 gene.
Calprotectin is a complex of the mammalian proteins S100A8 and S100A9. Other names for calprotectin include MRP8-MRP14, calgranulin A and B, cystic fibrosis antigen, L1, 60BB antigen, and 27E10 antigen. The proteins exist as homodimers but preferentially exist as S100A8/A9 heterodimers or heterotetramers (calprotectin) with antimicrobial, proinflammatory and prothrombotic properties. In the presence of calcium, calprotectin is capable of sequestering the transition metals iron, manganese and zinc via chelation. This metal sequestration affords the complex antimicrobial properties. Calprotectin is the only known antimicrobial manganese sequestration protein complex. Calprotectin comprises as much as 60% of the soluble protein content of the cytosol of a neutrophil, and it is secreted by an unknown mechanism during inflammation. Faecal calprotectin has been used to detect intestinal inflammation and can serve as a biomarker for inflammatory bowel diseases. Blood-based calprotectin is used in diagnostics of multiple inflammatory diseases, including autoimmune diseases, like arthritis, and severe infections including sepsis.
The epidermal differentiation complex (EDC) is a gene complex comprising over fifty genes encoding proteins involved in the terminal differentiation and cornification of keratinocytes, the primary cell type of the epidermis. In humans, the complex is located on a 1.9 Mbp stretch within chromosome 1q21. The proteins encoded by EDC genes are closely related in terms of function, and evolutionarily they belong to three distinct gene families: the cornified envelope precursor family, the S100 protein family and the S100 fused type protein (SFTP) family.
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