Protein S100-A9

Definition:

S100A9 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, adhesion, can increase the bactericidal activity of neutrophils by promoting phagocytosis via activation of SYK, PI3K/AKT, and ERK1/2 and can induce degranulation of neutrophils by a MAPK-dependent mechanism. 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, transferring 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 pro-inflammatory, antimicrobial, oxidant-scavenging and apoptosis-inducing activities. Its pro-inflammatory 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 pro-inflammatory 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. Has transnitrosylase activity; in oxidatively-modified low-densitity lipoprotein (LDL(ox))-induced S-nitrosylation of GAPDH on 'Cys-247' proposed to transfer the NO moiety from NOS2/iNOS to GAPDH via its own S-nitrosylated Cys-3. The iNOS-S100A8/A9 transnitrosylase complex is proposed to also direct selective inflammatory stimulus-dependent S-nitrosylation of multiple targets such as ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif.

References:

[1]. Jie Jia, et al. Target-selective protein S-nitrosylation by sequence motif recognition. Cell. 2014 Oct 23;159(3):623-34. [Content Brief]

[2]. Geetha Srikrishna, et al. S100A8 and S100A9: new insights into their roles in malignancy. J Innate Immun. 2012;4(1):31-40. [Content Brief]

[3]. Sylvie Berthier, et al. Molecular interface of S100A8 with cytochrome b558 and NADPH oxidase activation. PLoS One. 2012;7(7):e40277. [Content Brief]

[4]. Jean-Christophe Simard, et al. Induction of neutrophil degranulation by S100A9 via a MAPK-dependent mechanism. J Leukoc Biol. 2010 May;87(5):905-14. [Content Brief]

[5]. Thomas Vogl, et al. MRP8 and MRP14 control microtubule reorganization during transendothelial migration of phagocytes. Blood. 2004 Dec 15;104(13):4260-8. [Content Brief]

[6]. Matteo Riva, et al. Induction of nuclear factor-κB responses by the S100A9 protein is Toll-like receptor-4-dependent. Immunology. 2012 Oct;137(2):172-82. [Content Brief]

[7]. Mizhir Atallah, et al. Constitutive neutrophil apoptosis: regulation by cell concentration via S100 A8/9 and the MEK-ERK pathway. PLoS One. 2012;7(2):e29333. [Content Brief]

[8]. Thomas Vogl, et al. Pro-inflammatory S100A8 and S100A9 proteins: self-assembly into multifunctional native and amyloid complexes. Int J Mol Sci. 2012;13(3):2893-2917. [Content Brief]

[9]. Chunsun Li, et al. A novel p53 target gene, S100A9, induces p53-dependent cellular apoptosis and mediates the p53 apoptosis pathway. Biochem J. 2009 Aug 13;422(2):363-72. [Content Brief]

[10]. Claus Kerkhoff, et al. 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. [Content Brief]

[11]. Dorothee Viemann, et al. Myeloid-related proteins 8 and 14 induce a specific inflammatory response in human microvascular endothelial cells. Blood. 2005 Apr 1;105(7):2955-62. [Content Brief]

[12]. Per Björk, et al. Identification of human S100A9 as a novel target for treatment of autoimmune disease via binding to quinoline-3-carboxamides. PLoS Biol. 2009 Apr 28;7(4):e97. [Content Brief]

[13]. Carle Ryckman, et al. Proinflammatory activities of S100: proteins S100A8, S100A9, and S100A8/A9 induce neutrophil chemotaxis and adhesion. J Immunol. 2003 Mar 15;170(6):3233-42. [Content Brief]

[14]. Saeid Ghavami, et al. 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. [Content Brief]

[15]. Chantrakorn Champaiboon, et al. 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. [Content Brief]

[16]. Jean-Christophe Simard, et al. Damage-associated molecular pattern S100A9 increases bactericidal activity of human neutrophils by enhancing phagocytosis. J Immunol. 2011 Mar 15;186(6):3622-31. [Content Brief]

[17]. K T Miyasaki, et al. In vitro antimicrobial activity of the human neutrophil cytosolic S-100 protein complex, calprotectin, against Capnocytophaga sputigena. J Dent Res. 1993 Feb;72(2):517-23. [Content Brief]

[18]. Yuichi Nakatani, et al. 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. [Content Brief]

[19]. Akiko Koike, et al. 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. [Content Brief]

[20]. Herve Y Sroussi, et al. 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. [Content Brief]

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