Biology:S100A9

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1]

The proteins S100A8 and S100A9 form a heterodimer called calprotectin.

Function

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.[1]

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)[2][3] and the receptor for advanced glycation end products.[4]

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. [5] 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. [5][6]

Clinical significance

Altered expression of the S100A9 protein is associated with the disease cystic fibrosis.[1]

MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury by promoting leukocyte recruitment.[7]

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.[8] 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.[9]

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.[10][11] 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.[12] 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;[13] 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.[13]

Animal studies

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.[14] This mouse line has been used to study the role of S100A9 and S100A8 in a number of experimental inflammatory conditions.

See also

  • S-100 protein

References

  1. ↑ 1.0 1.1 1.2 "Entrez Gene: S100A9 S100 calcium binding protein A9". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6280. 
  2. ↑ "Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock". Nat. Med. 13 (9): 1042–9. September 2007. doi:10.1038/nm1638. PMID 17767165. 
  3. ↑ "RAGE and TLRs: relatives, friends or neighbours?". Molecular Immunology 56 (4): 739–44. 2013. doi:10.1016/j.molimm.2013.07.008. PMID 23954397. 
  4. ↑ "S100A8 and S100A9 mediate endotoxin-induced cardiomyocyte dysfunction via the receptor for advanced glycation end products". Circ. Res. 102 (10): 1239–46. May 2008. doi:10.1161/CIRCRESAHA.107.167544. PMID 18403730. 
  5. ↑ 5.0 5.1 "Neutrophil extracellular traps enhance macrophage killing of bacterial pathogens" (in EN). Science Advances 7 (37): eabj2101. September 2021. doi:10.1126/sciadv.abj2101. PMID 34516771. Bibcode: 2021SciA....7.2101M. 
  6. ↑ "Dietary Manganese Promotes Staphylococcal Infection of the Heart". Cell Host & Microbe 22 (4): 531–542.e8. October 2017. doi:10.1016/j.chom.2017.08.009. PMID 28943329. 
  7. ↑ "MRP-8/14 is Critical for the Biological Response to Vascular Injury". Circulation 120 (5): 427–36. August 2009. doi:10.1161/CIRCULATIONAHA.108.814582. PMID 19620505. 
  8. ↑ "Myeloid-Related Protein-8/14 and the Risk of Cardiovascular Death or Myocardial Infarction after an Acute Coronary Syndrome in the PROVE IT-TIMI 22 Trial". Am. Heart J. 155 (1): 49–55. January 2008. doi:10.1016/j.ahj.2007.08.018. PMID 18082488. 
  9. ↑ "Platelet expression profiling and clinical validation of myeloid-related protein-14 as a novel determinant of cardiovascular events". Circulation 113 (19): 2278–84. May 2006. doi:10.1161/CIRCULATIONAHA.105.607333. PMID 16682612. 
  10. ↑ "Inhibition of dendritic cell differentiation and accumulation of myeloid-derived suppressor cells in cancer is regulated by S100A9 protein". J. Exp. Med. 205 (10): 2235–49. September 2008. doi:10.1084/jem.20080132. PMID 18809714. 
  11. ↑ "S100-A9 protein in exosomes from chronic lymphocytic leukemia cells promotes NF-κB activity during disease progression". Blood 130 (6): 777–788. 2017. doi:10.1182/blood-2017-02-769851. PMID 28596424. 
  12. ↑ "Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis". Nat. Cell Biol. 8 (12): 1369–75. December 2006. doi:10.1038/ncb1507. PMID 17128264. 
  13. ↑ 13.0 13.1 "Myeloid-related protein (MRP)-8 from cervico-vaginal secretions activates HIV replication". AIDS 15 (4): 441–9. 2001. doi:10.1097/00002030-200103090-00002. PMID 11242140. 
  14. ↑ "Loss of S100A9 (MRP14) Results in Reduced Interleukin-8-Induced CD11b Surface Expression, a Polarized Microfilament System, and Diminished Responsiveness to Chemoattractants In Vitro". Mol. Cell. Biol. 23 (3): 1034–43. February 2003. doi:10.1128/MCB.23.3.1034-1043.2003. PMID 12529407. 

Further reading



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