S100A9
Description
The S100A9 (S100 calcium binding protein A9) is a protein-coding gene located on chromosome 1.
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. 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. 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) and the receptor for advanced glycation end products. 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. 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.
S100A9 is a calcium- and zinc-binding protein that plays a key role in regulating inflammatory processes and immune responses. It can induce neutrophil chemotaxis and adhesion, enhance their bactericidal activity by promoting phagocytosis through activation of SYK, PI3K/AKT, and ERK1/2 pathways, and trigger neutrophil degranulation via a MAPK-dependent mechanism. S100A9 is often found as a heterodimer with S100A8, forming calprotectin, which has a wide range of both intracellular and extracellular functions. Intracellularly, calprotectin facilitates leukocyte arachidonic acid trafficking and metabolism, regulates the tubulin-dependent cytoskeleton during phagocyte migration, and activates the neutrophilic NADPH-oxidase. It activates NADPH-oxidase by assisting in the assembly of the enzyme complex at the cell membrane, transferring arachidonic acid, an essential cofactor, to the complex. S100A8 further contributes to this assembly by directly binding to NCF2/P67PHOX. Extracellularly, calprotectin exhibits pro-inflammatory, antimicrobial, oxidant-scavenging, and apoptosis-inducing activities. Its pro-inflammatory actions include recruiting leukocytes, promoting cytokine and chemokine production, and regulating leukocyte adhesion and migration. Acting as an alarmin or a DAMP molecule, it stimulates innate immune cells by binding to pattern recognition receptors like TLR4 and AGER. This binding activates MAP-kinase and NF-kappa-B signaling pathways, amplifying the pro-inflammatory cascade. Calprotectin possesses antimicrobial activity against bacteria and fungi, likely achieved through chelation of Zn(2+), which is essential for microbial growth. It can induce cell death via autophagy and apoptosis, mediated by the interplay between mitochondria and lysosomes through reactive oxygen species (ROS) and involving BNIP3. Calprotectin can regulate neutrophil numbers and apoptosis via an anti-apoptotic effect, controlling cell survival through ITGAM/ITGB and TLR4, and a signaling mechanism involving MEK-ERK. Its role as an oxidant scavenger helps prevent excessive tissue damage by neutralizing oxidants. Calprotectin can amplify inflammation in autoimmune diseases and cancer development and spread. It exhibits transnitrosylase activity, transferring the NO moiety from NOS2/iNOS to GAPDH via its own S-nitrosylated Cys-3. The iNOS-S100A8/A9 transnitrosylase complex is suggested to also direct selective inflammatory stimulus-dependent S-nitrosylation of various targets, like ANXA5, EZR, MSN, and VIM, by recognizing a [IL]-x-C-x-x-[DE] motif.
S100A9 is also known as 60B8AG, CAGB, CFAG, CGLB, L1AG, LIAG, MAC387, MIF, MRP14, NIF, P14, S100-A9.
