8sjc

Structural highlights

Function

S10A8_HUMAN S100A8 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response. It can induce neutrophil chemotaxis and adhesion. Predominantly found as calprotectin (S100A8/A9) which has a wide plethora of intra- and extracellular functions. The intracellular functions include: facilitating leukocyte arachidonic acid trafficking and metabolism, modulation of the tubulin-dependent cytoskeleton during migration of phagocytes and activation of the neutrophilic NADPH-oxidase. Activates NADPH-oxidase by facilitating the enzyme complex assembly at the cell membrane, transfering arachidonic acid, an essential cofactor, to the enzyme complex and S100A8 contributes to the enzyme assembly by directly binding to NCF2/P67PHOX. The extracellular functions involve proinfammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its proinflammatory activity includes recruitment of leukocytes, promotion of cytokine and chemokine production, and regulation of leukocyte adhesion and migration. Acts as an alarmin or a danger associated molecular pattern (DAMP) molecule and stimulates innate immune cells via binding to pattern recognition receptors such as Toll-like receptor 4 (TLR4) and receptor for advanced glycation endproducts (AGER). Binding to TLR4 and AGER activates the MAP-kinase and NF-kappa-B signaling pathways resulting in the amplification of the proinflammatory cascade. Has antimicrobial activity towards bacteria and fungi and exerts its antimicrobial activity probably via chelation of Zn(2+) which is essential for microbial growth. Can induce cell death via autophagy and apoptosis and this occurs through the cross-talk of mitochondria and lysosomes via reactive oxygen species (ROS) and the process involves BNIP3. Can regulate neutrophil number and apoptosis by an anti-apoptotic effect; regulates cell survival via ITGAM/ITGB and TLR4 and a signaling mechanism involving MEK-ERK. Its role as an oxidant scavenger has a protective role in preventing exaggerated tissue damage by scavenging oxidants. Can act as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread.^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]}

References

1. ↑ Ryckman C, Vandal K, Rouleau P, Talbot M, Tessier PA. Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. J Immunol. 2003 Mar 15;170(6):3233-42. PMID:12626582
2. ↑ Vogl T, Ludwig S, Goebeler M, Strey A, Thorey IS, Reichelt R, Foell D, Gerke V, Manitz MP, Nacken W, Werner S, Sorg C, Roth J. MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes. Blood. 2004 Dec 15;104(13):4260-8. Epub 2004 Aug 26. PMID:15331440 doi:10.1182/blood-2004-02-0446
3. ↑ Viemann D, Strey A, Janning A, Jurk K, Klimmek K, Vogl T, Hirono K, Ichida F, Foell D, Kehrel B, Gerke V, Sorg C, Roth J. Myeloid-related proteins 8 and 14 induce a specific inflammatory response in human microvascular endothelial cells. Blood. 2005 Apr 1;105(7):2955-62. Epub 2004 Dec 14. PMID:15598812 doi:10.1182/blood-2004-07-2520
4. ↑ Kerkhoff C, Nacken W, Benedyk M, Dagher MC, Sopalla C, Doussiere J. The arachidonic acid-binding protein S100A8/A9 promotes NADPH oxidase activation by interaction with p67phox and Rac-2. FASEB J. 2005 Mar;19(3):467-9. Epub 2005 Jan 10. PMID:15642721 doi:10.1096/fj.04-2377fje
5. ↑ Nakatani Y, Yamazaki M, Chazin WJ, Yui S. Regulation of S100A8/A9 (calprotectin) binding to tumor cells by zinc ion and its implication for apoptosis-inducing activity. Mediators Inflamm. 2005 Oct 24;2005(5):280-92. PMID:16258195 doi:10.1155/MI.2005.280
6. ↑ Sroussi HY, Kohler GA, Agabian N, Villines D, Palefsky JM. Substitution of methionine 63 or 83 in S100A9 and cysteine 42 in S100A8 abrogate the antifungal activities of S100A8/A9: potential role for oxidative regulation. FEMS Immunol Med Microbiol. 2009 Jan;55(1):55-61. doi:, 10.1111/j.1574-695X.2008.00498.x. Epub 2008 Dec 11. PMID:19087201 doi:10.1111/j.1574-695X.2008.00498.x
7. ↑ Champaiboon C, Sappington KJ, Guenther BD, Ross KF, Herzberg MC. Calprotectin S100A9 calcium-binding loops I and II are essential for keratinocyte resistance to bacterial invasion. J Biol Chem. 2009 Mar 13;284(11):7078-90. doi: 10.1074/jbc.M806605200. Epub 2009 , Jan 3. PMID:19122197 doi:10.1074/jbc.M806605200
8. ↑ Ghavami S, Eshragi M, Ande SR, Chazin WJ, Klonisch T, Halayko AJ, McNeill KD, Hashemi M, Kerkhoff C, Los M. S100A8/A9 induces autophagy and apoptosis via ROS-mediated cross-talk between mitochondria and lysosomes that involves BNIP3. Cell Res. 2010 Mar;20(3):314-31. doi: 10.1038/cr.2009.129. Epub 2009 Nov 24. PMID:19935772 doi:10.1038/cr.2009.129
9. ↑ Koike A, Arai S, Yamada S, Nagae A, Saita N, Itoh H, Uemoto S, Totani M, Ikemoto M. Dynamic mobility of immunological cells expressing S100A8 and S100A9 in vivo: a variety of functional roles of the two proteins as regulators in acute inflammatory reaction. Inflammation. 2012 Apr;35(2):409-19. doi: 10.1007/s10753-011-9330-8. PMID:21487906 doi:10.1007/s10753-011-9330-8
10. ↑ Berthier S, Nguyen MV, Baillet A, Hograindleur MA, Paclet MH, Polack B, Morel F. Molecular interface of S100A8 with cytochrome b558 and NADPH oxidase activation. PLoS One. 2012;7(7):e40277. doi: 10.1371/journal.pone.0040277. Epub 2012 Jul 10. PMID:22808130 doi:10.1371/journal.pone.0040277
11. ↑ Atallah M, Krispin A, Trahtemberg U, Ben-Hamron S, Grau A, Verbovetski I, Mevorach D. Constitutive neutrophil apoptosis: regulation by cell concentration via S100 A8/9 and the MEK-ERK pathway. PLoS One. 2012;7(2):e29333. doi: 10.1371/journal.pone.0029333. Epub 2012 Feb 17. PMID:22363402 doi:10.1371/journal.pone.0029333