The protein encoded by this gene 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 and as a cytokine. Altered expression of this protein is associated with the disease cystic fibrosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]
Full Name
S100 Calcium Binding Protein A8
Function
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, 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 Zn2+ 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. The iNOS-S100A8/A9 transnitrosylase complex directs selective inflammatory stimulus-dependent S-nitrosylation of GAPDH and probably multiple targets such as ANXA5, EZR, MSN and VIM by recognizing a [IL]-x-C-x-x-[DE] motif; S100A8 seems to contribute to S-nitrosylation site selectivity. (Microbial infection) Upon infection by human coronavirus SARS-CoV-2, may induce expansion of aberrant immature neutrophils in a TLR4-dependent manner.
Biological Process
Biological Process activation of cysteine-type endopeptidase activity involved in apoptotic processManual Assertion Based On ExperimentIDA:UniProtKB Biological Process acute inflammatory responseIEA:Ensembl Biological Process apoptotic processIEA:UniProtKB-KW Biological Process astrocyte developmentIEA:Ensembl Biological Process autocrine signalingIEA:Ensembl Biological Process autophagyManual Assertion Based On ExperimentIDA:UniProtKB Biological Process chronic inflammatory responseIEA:Ensembl Biological Process defense response to bacteriumManual Assertion Based On ExperimentTAS:UniProtKB Biological Process defense response to fungusManual Assertion Based On ExperimentTAS:UniProtKB Biological Process inflammatory responseManual Assertion Based On ExperimentTAS:ProtInc Biological Process innate immune responseIEA:UniProtKB-KW Biological Process leukocyte migration involved in inflammatory responseManual Assertion Based On ExperimentIDA:UniProtKB Biological Process neutrophil aggregationManual Assertion Based On ExperimentIDA:UniProtKB Biological Process neutrophil chemotaxisManual Assertion Based On ExperimentIDA:UniProtKB Biological Process peptide secretionIEA:Ensembl Biological Process peptidyl-cysteine S-nitrosylationManual Assertion Based On ExperimentIMP:UniProtKB Biological Process positive regulation of cell growthManual Assertion Based On ExperimentTAS:UniProtKB Biological Process positive regulation of inflammatory responseManual Assertion Based On ExperimentIDA:UniProtKB Biological Process positive regulation of intrinsic apoptotic signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB Biological Process positive regulation of NF-kappaB transcription factor activityManual Assertion Based On ExperimentTAS:UniProtKB Biological Process positive regulation of peptide secretionIEA:Ensembl Biological Process regulation of cytoskeleton organizationManual Assertion Based On ExperimentTAS:UniProtKB Biological Process response to ethanolIEA:Ensembl Biological Process response to lipopolysaccharideManual Assertion Based On ExperimentIBA:GO_Central Biological Process response to zinc ionIEA:Ensembl Biological Process sequestering of zinc ionManual Assertion Based On ExperimentTAS:UniProtKB Biological Process wound healingIEA:Ensembl
Cellular Location
Secreted Cytoplasm Cytoplasm, cytoskeleton Cell membrane Predominantly localized in the cytoplasm. Upon elevation of the intracellular calcium level, translocated from the cytoplasm to the cytoskeleton and the cell membrane. Upon neutrophil activation or endothelial adhesion of monocytes, is secreted via a microtubule-mediated, alternative pathway.
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