S100A8

Summary

S100A8 (S100 calcium binding protein A8, HGNC:10498) is a protein-coding gene on chromosome 1q21.3, encoding Protein S100-A8 (P05109). S100A8 is a calcium- and zinc-binding protein which plays a prominent role in the regulation of inflammatory processes and immune response.

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.

Source: NCBI Gene 6279 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 5 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002964

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10498
Approved symbol	S100A8
Name	S100 calcium binding protein A8
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	P8, MRP8, MRP-8, 60B8AG, CGLA, S100-A8
Ensembl gene	ENSG00000143546
Ensembl biotype	protein_coding
OMIM	123885
Entrez	6279

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000368732, ENST00000368733, ENST00000477801, ENST00000909750, ENST00000909751, ENST00000955442, ENST00000955443

RefSeq mRNA: 5 — MANE Select: NM_002964 NM_001319196, NM_001319197, NM_001319198, NM_001319201, NM_002964

CCDS: CCDS1038

Canonical transcript exons

ENST00000368733 — 3 exons

Exon	Start	End
ENSE00001447864	153390032	153390243
ENSE00001447867	153390395	153390557
ENSE00001447868	153391041	153391073

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 100.00.

FANTOM5 (CAGE): breadth broad, TPM avg 412.0083 / max 205910.5679, expressed in 535 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14622	409.7834	534
14621	1.0489	139
14620	0.5091	97
14616	0.3796	77
14617	0.1931	57
14618	0.0699	20
14619	0.0242	8

Top tissues by expression

291 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pharyngeal mucosa	UBERON:0000355	100.00	gold quality
monocyte	CL:0000576	99.99	gold quality
mononuclear cell	CL:0000842	99.99	gold quality
oral cavity	UBERON:0000167	99.99	gold quality
gingiva	UBERON:0001828	99.99	gold quality
gingival epithelium	UBERON:0001949	99.99	gold quality
trabecular bone tissue	UBERON:0002483	99.99	gold quality
tongue squamous epithelium	UBERON:0006919	99.99	gold quality
periodontal ligament	UBERON:0008266	99.99	gold quality
body of tongue	UBERON:0011876	99.99	gold quality
lower esophagus mucosa	UBERON:0035834	99.99	gold quality
leukocyte	CL:0000738	99.98	gold quality
mammalian vulva	UBERON:0000997	99.98	gold quality
bone marrow	UBERON:0002371	99.98	gold quality
cervix squamous epithelium	UBERON:0006922	99.98	gold quality
palpebral conjunctiva	UBERON:0001812	99.97	gold quality
granulocyte	CL:0000094	99.96	gold quality
penis	UBERON:0000989	99.96	gold quality
tongue	UBERON:0001723	99.96	gold quality
bone marrow cell	CL:0002092	99.95	gold quality
cervix epithelium	UBERON:0004801	99.95	gold quality
squamous epithelium	UBERON:0006914	99.94	gold quality
buccal mucosa cell	CL:0002336	99.93	gold quality
esophagus mucosa	UBERON:0002469	99.91	gold quality
esophagus squamous epithelium	UBERON:0006920	99.91	gold quality
superior surface of tongue	UBERON:0007371	99.91	gold quality
blood	UBERON:0000178	99.85	gold quality
spleen	UBERON:0002106	99.85	gold quality
right lung	UBERON:0002167	99.81	gold quality
epithelium of esophagus	UBERON:0001976	99.66	gold quality

Single-cell (SCXA)

Detected in 47 experiment(s), a significant marker in 43.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	209146.11
E-HCAD-1	yes	98630.31
E-GEOD-149689	yes	80644.88
E-ANND-2	yes	70461.53
E-HCAD-10	yes	67203.56
E-MTAB-9221	yes	62121.24
E-MTAB-7407	yes	57589.36
E-MTAB-10432	yes	55359.70
E-MTAB-10042	yes	53792.65
E-MTAB-8142	yes	51270.12
E-CURD-55	yes	50516.05
E-HCAD-4	yes	38601.11
E-GEOD-150728	yes	38588.46
E-CURD-122	yes	37509.25
E-GEOD-139324	yes	36903.48

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, CEBPB, CEBPE, CEBPG, HIF1A, IRF6, MYOD1, ONECUT1, SP1

Literature-anchored findings (GeneRIF, showing 40)

• examination of whether the prevalence of somatic p53 mutation in gastric adenocarcinoma differed between subjects with and without infection with CagA(+) (a marker for the PAI) H. pylori strains (PMID:11895856)
• These data indicate that calprotectin (MRP8 and MRP14)has higher specific activity to induce apoptosis than the individual subunits, and that the mechanism is exclusion of zinc from target cells. (PMID:12137245)
• Proinflammatory myeloid-related protein S100A8 induces a dose- and time-dependent activation of the HIV-1 long terminal repeat promoter region that can be blocked by specific polyclonal antibody and by physical denaturation of the protein. (PMID:12218151)
• Extensive expression of S100A8 and S100A9 defines a novel inflammatory disorder. (PMID:12480428)
• S100A8 and S100A9 calcium-binding proteins: localization within normal and cyclosporin A-induced overgrowth gingiva, in spino-cellular layer and extracellularly in desmosomes, in cytoplasm and nuclei. (PMID:12489193)
• S100A8 stimulates shedding of L-selectin, up-regulates and activates Mac-1/CD11b, induces neutrophil adhesion to fibrinogen in vitro, and is involved in neutrophil migration to in vivo inflammatory sites. (PMID:12626582)
• plays a prominent role in leukocyte trafficking and arachidonic acid metabolism; elevated levels of S100A8 and S100A9 in body fluids of inflamed tissues strengthen the view that these molecules are important players in fighting inflammation [review] (PMID:12645005)
• S100A8 and S100A9 induce inflammatory activation of endothelial cells [review]. (PMID:12697438)
• increased levels in fetal disease, premature rupture of membranes, and preterm labor (PMID:12710851)
• MRP8/MRP14 dimer behaves as a positive mediator of phagocyte NADPH oxidase regulation (PMID:12719414)
• Activated macrophages can promote destruction and impair regeneration of myocytes during the course of inflammatory myopathies via secretion of S100A8 and S100A9. (PMID:12937135)
• Since MRP-8/MRP-14 exhibit direct effects on leukocyte adhesion to the vascular endothelium, their extensive expression in the epidermis indicates an active role for these S-100 proteins in the initial phase of this systemic autoimmune disease. (PMID:13130482)
• decreased expression of MRP8 and MRP14 might play an important role in the pathogenesis of human esophageal squamous cell carcinoma, being particularly associated with poor differentiation of tumor cells. (PMID:15069705)
• Fibronectin adhesive capacity and integrin expression of monocytes of type 1 and type 2 diabetic patients is related to the subjects’ serum levels of MRP-8. (PMID:15277376)
• Phosphorylation inhibits tubulin polymerization in microtubules. (PMID:15331440)
• The complex of S100A8 and S100A9 promotes tubulin polymerization and integrates mitogen-activated protein kinase- and calcium-dependent signals during migration of phagocytes. (PMID:15331440)
• expression of MRP8/MRP14 closely correlated with the inflammatory activity in systemic vasculitis (PMID:15598812)
• S100A8/A9 promotes phagocyte NADPH oxidase activation by supplying the enzyme with its cofactor arachidonic acid (PMID:15642721)
• Calgranulin A and chaperonin 10 are identified as markers for diagnosis and screening of endometrial carcinoma. (PMID:15816004)
• data suggest that enhanced expression of S100A8, S100A9, and RAGE is an early event in prostate tumorigenesis and may contribute to development and progression or extension of prostate carcinomas (PMID:16033829)
• S100A8 and S100A9 in atherosclerotic plaque and calcifying matrix vesicles may significantly influence redox- and Ca2+-dependent processes during atherogenesis (PMID:16216873)
• heterodimeric S100 calcium binding protein A8/S100 calcium binding protein A9 might play a hitherto unknown role in triggering atherosclerosis in diabetes and renal failure (PMID:16573830)
• S100A8/A9 heterodimer, secreted extracellularly from activated tissue macrophages, may amplify proinflammatory cytokine responses in rheumatoid arthritis. (PMID:16613612)
• calcium-dependent formation of (S100A8/S100A9)2 tetramers is an essential prerequisite for biological function. (PMID:16690079)
• MRP-8/14 was mainly detected in human cervical mucus and showed a positive correlation with proinflammatory cytokines (PMID:16806487)
• MRP-8/MRP-14 are exclusively secreted by granulocytes in patients with acute Kawasaki disease, and intravenous immune globulin treatment suppresses their gene expression. (PMID:16979015)
• Zinc-binding, like calcium, induces (S100A8/S100A9)(2)-tetramers. (PMID:17050004)
• The G+ genotype/G allele may be considered to exert a significant protective effect in males against aggressive periodontitis. (PMID:17069562)
• S100A8 and S100A9 are involved in the innate defense of the bronchial epithelium (PMID:17090475)
• Excessive release of cytotoxic MRP8/MRP14 by activated phagocytes might therefore present an important molecular pathomechanism contributing to endothelial damage during vasculitis and other inflammatory diseases (PMID:17095618)
• the effect of calcium on telomerase in the human epidermal keratinocyte line HaCaT showed calcium directly interacts with the telomerase complex. This interaction could be mediated by the calcium-binding protein S100A8 (PMID:17197440)
• HaCaT keratinocytes overexpressing the S100 proteins S100A8 and S100A9 show increased NADPH oxidase and NF-kappaB activities. (PMID:17429438)
• Correlation of the expression of S100A8 and S100A9 revealed that the microenvironments of tumours which lacked expression of Smad4, had significantly reduced numbers of S100A8-immunoreactive (p = 0.023) but not S100A9-immunoreactive (p = 0.21) cells. (PMID:17469085)
• mechanism of S100A8 in the oncogenesis and development of laryngeal cancer (PMID:17557234)
• Report showed S100A8 was expressed human bone and cartilage cells and may contribute to calcification of the cartilage matrix and its replacement with trabecular bone, and to regulation of redox in bone resorption. (PMID:17636430)
• S100A8 is regulated by IL-17, dexamethasone, IL-4 and IL-13 in HaCat cells (human keratinocyte cell line) (PMID:17644317)
• Data suggest that S100 proteins calprotectin and S100A12 are related to radiographic changes rather than disease activity in psoriatic arthritis with low disease activity. (PMID:17787039)
• Serum calprotectin (S100A8/S100A9)and S100A12 are increased in children with inflammatory bowel disease and indicate disease activity. (PMID:17852869)
• MRP8/14 may be involved in the pathogenesis of sarcoid granulomas. The measurement of serum MRP8/14 levels is useful for the diagnosis of sarcoidosis. (PMID:17895549)
• The homo-oligomeric forms of S100A8 and S100A9 are readily degraded by proteases, and the preferred hetero-oligomeric S100A8/A9 complex displays a high resistance even against proteinase K degradation. (PMID:17936757)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	s100s	ENSDARG00000036773
danio_rerio	s100a10a	ENSDARG00000037425
danio_rerio	s100t	ENSDARG00000055589
mus_musculus	S100a8	ENSMUSG00000056054
rattus_norvegicus	S100a8	ENSRNOG00000011557

Paralogs (21): CRNN (ENSG00000143536), S100A7 (ENSG00000143556), S100B (ENSG00000160307), S100A1 (ENSG00000160678), S100A11 (ENSG00000163191), S100A9 (ENSG00000163220), S100A12 (ENSG00000163221), S100P (ENSG00000163993), S100G (ENSG00000169906), S100Z (ENSG00000171643), S100A7A (ENSG00000184330), S100A3 (ENSG00000188015), S100A16 (ENSG00000188643), SNTN (ENSG00000188817), S100A13 (ENSG00000189171), S100A14 (ENSG00000189334), S100A4 (ENSG00000196154), S100A5 (ENSG00000196420), S100A2 (ENSG00000196754), S100A10 (ENSG00000197747), S100A6 (ENSG00000197956)

Protein

Protein identifiers

Protein S100-A8 — P05109 (reviewed: P05109)

Alternative names: Calgranulin-A, Calprotectin L1L subunit, Cystic fibrosis antigen, Leukocyte L1 complex light chain, Migration inhibitory factor-related protein 8, S100 calcium-binding protein A8, Urinary stone protein band A

All UniProt accessions (1): P05109

UniProt curated annotations — full annotation on UniProt →

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. Also participates in regulatory T-cell differentiation together with CD69. 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. 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.

Subunit / interactions. Homodimer. Preferentially exists as a heterodimer or heterotetramer with S100A9 known as calprotectin (S100A8/A9). S100A8 interacts with AGER, ATP2A2 and with the heterodimeric complex formed by TLR4 and LY96. Interacts with GAPDH. Calprotectin (S100A8/9) interacts with CEACAM3 and tubulin filaments in a calcium-dependent manner. Heterotetrameric calprotectin (S100A8/A9) interacts with ANXA6 and associates with tubulin filaments in activated monocytes. S100A8 and calprotectin (S100A8/9) interact with NCF2/P67PHOX, RAC1 and RAC2. Calprotectin (S100A8/9) interacts with CYBA and CYBB. Calprotectin (S100A8/9) interacts with NOS2 to form the iNOS-S100A8/A9 transnitrosylase complex; induced by LDL(ox). Calprotectin (S100A8/9) interacts with CD69.

Subcellular location. Secreted. Cytoplasm. Cytoskeleton. Cell membrane.

Tissue specificity. Calprotectin (S100A8/9) is predominantly expressed in myeloid cells. Except for inflammatory conditions, the expression is restricted to a specific stage of myeloid differentiation since both proteins are expressed in circulating neutrophils and monocytes but are absent in normal tissue macrophages and lymphocytes. Under chronic inflammatory conditions, such as psoriasis and malignant disorders, also expressed in the epidermis. Found in high concentrations at local sites of inflammation or in the serum of patients with inflammatory diseases such as rheumatoid, cystic fibrosis, inflammatory bowel disease, Crohn’s disease, giant cell arteritis, cystic fibrosis, Sjogren’s syndrome, systemic lupus erythematosus, and progressive systemic sclerosis. Involved in the formation and deposition of amyloids in the aging prostate known as corpora amylacea inclusions. Strongly up-regulated in many tumors, including gastric, esophageal, colon, pancreatic, bladder, ovarian, thyroid, breast and skin cancers.

Activity regulation. Calprotectin (S100A8/A9) activity on TLR4 signaling is inhibited by paquinimod.

Induction. (Microbial infection) Expression is highly induced in CD14(+) monocytes, neutrophils, and developing neutrophils of patients infected by SARS-COV-2.

Miscellaneous. Binds two calcium ions per molecule with an affinity similar to that of the S100 proteins.

Similarity. Belongs to the S-100 family.

RefSeq proteins (5): NP_001306125, NP_001306126, NP_001306127, NP_001306130, NP_002955* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001751	S100/CaBP7/8-like_CS	Conserved_site
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR013787	S100_Ca-bd_sub	Domain
IPR018247	EF_Hand_1_Ca_BS	Binding_site

Pfam: PF01023

UniProt features (22 total): binding site 9, helix 5, domain 2, strand 2, chain 1, modified residue 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

13 structures.

PDB	Method	Resolution (Å)
4GGF	X-RAY DIFFRACTION	1.6
9ON4	X-RAY DIFFRACTION	1.66
8SJB	X-RAY DIFFRACTION	1.74
4XJK	X-RAY DIFFRACTION	1.76
1XK4	X-RAY DIFFRACTION	1.8
7QUV	X-RAY DIFFRACTION	1.85
8SJC	X-RAY DIFFRACTION	1.87
1MR8	X-RAY DIFFRACTION	1.9
5HLO	X-RAY DIFFRACTION	2.1
6DS2	X-RAY DIFFRACTION	2.1
5HLV	X-RAY DIFFRACTION	2.2
5W1F	X-RAY DIFFRACTION	2.6
9OAA	ELECTRON MICROSCOPY	3.67

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05109-F1	92.74	0.84

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (9): 83; 87; 17; 27; 33; 59; 61; 63; 70

Post-translational modifications (1): 42

Mutagenesis-validated functional residues (1):

Position	Phenotype
42	loss of antifungal activity.

Function

Pathways and Gene Ontology

Reactome pathways

26 pathways

ID	Pathway
R-HSA-1236974	ER-Phagosome pathway
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-5602498	MyD88 deficiency (TLR2/4)
R-HSA-5603041	IRAK4 deficiency (TLR2/4)
R-HSA-5668599	RHO GTPases Activate NADPH Oxidases
R-HSA-5686938	Regulation of TLR by endogenous ligand
R-HSA-6798695	Neutrophil degranulation
R-HSA-6799990	Metal sequestration by antimicrobial proteins
R-HSA-1236975	Antigen processing-Cross presentation
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade
R-HSA-168188	Toll Like Receptor TLR6:TLR2 Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-181438	Toll Like Receptor 2 (TLR2) Cascade
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-5260271	Diseases of Immune System
R-HSA-5602358	Diseases associated with the TLR signaling cascade
R-HSA-6803157	Antimicrobial peptides
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 450 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GSE45365_NK_CELL_VS_BCELL_UP, SHEPARD_BMYB_MORPHOLINO_UP, DAVIES_MULTIPLE_MYELOMA_VS_MGUS_DN, GOBP_RESPONSE_TO_ETHANOL, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_ZINC_ION, MYOGENIN_Q6, MCLACHLAN_DENTAL_CARIES_UP, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, JAEGER_METASTASIS_DN

GO Biological Process (26): leukocyte migration involved in inflammatory response (GO:0002523), chronic inflammatory response (GO:0002544), peptide secretion (GO:0002790), positive regulation of peptide secretion (GO:0002793), autophagy (GO:0006914), apoptotic process (GO:0006915), inflammatory response (GO:0006954), response to zinc ion (GO:0010043), astrocyte development (GO:0014002), peptidyl-cysteine S-nitrosylation (GO:0018119), positive regulation of cell growth (GO:0030307), neutrophil chemotaxis (GO:0030593), response to lipopolysaccharide (GO:0032496), regulation of toll-like receptor signaling pathway (GO:0034121), autocrine signaling (GO:0035425), defense response to bacterium (GO:0042742), endothelial cell migration (GO:0043542), innate immune response (GO:0045087), response to ethanol (GO:0045471), positive regulation of inflammatory response (GO:0050729), defense response to fungus (GO:0050832), regulation of cytoskeleton organization (GO:0051493), neutrophil aggregation (GO:0070488), positive regulation of intrinsic apoptotic signaling pathway (GO:2001244), immune system process (GO:0002376), chemotaxis (GO:0006935)

GO Molecular Function (9): calcium ion binding (GO:0005509), microtubule binding (GO:0008017), zinc ion binding (GO:0008270), Toll-like receptor 4 binding (GO:0035662), calcium-dependent protein binding (GO:0048306), arachidonate binding (GO:0050544), RAGE receptor binding (GO:0050786), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (14): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), extracellular matrix (GO:0031012), secretory granule lumen (GO:0034774), intermediate filament cytoskeleton (GO:0045111), extracellular exosome (GO:0070062), calprotectin complex (GO:1990660), S100A8 complex (GO:1990661), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Toll-like Receptor Cascades	3
Diseases associated with the TLR signaling cascade	2
Innate Immune System	2
Immune System	2
Toll Like Receptor 2 (TLR2) Cascade	2
Antigen processing-Cross presentation	1
Toll Like Receptor 4 (TLR4) Cascade	1
Toll Like Receptor TLR1:TLR2 Cascade	1
Toll Like Receptor TLR6:TLR2 Cascade	1
RHO GTPase Effectors	1
Antimicrobial peptides	1
Class I MHC mediated antigen processing & presentation	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
inflammatory response	3
defense response	2
protein-containing complex	2
leukocyte migration	1
peptide transport	1
secretion	1
peptide secretion	1
regulation of peptide secretion	1
positive regulation of secretion	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
response to metal ion	1
glial cell development	1
astrocyte differentiation	1
protein nitrosylation	1
peptidyl-cysteine modification	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
granulocyte chemotaxis	1
neutrophil migration	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
toll-like receptor signaling pathway	1
regulation of pattern recognition receptor signaling pathway	1
cell-cell signaling	1
response to bacterium	1
cell migration	1
immune response	1
defense response to symbiont	1
response to alcohol	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1

Protein interactions and networks

STRING

3033 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
S100A8	PTPN11	Q06124	995
S100A8	S100A9	P06702	989
S100A8	TJP1	Q07157	980
S100A8	CDH1	P12830	944
S100A8	MET	P08581	920
S100A8	GRB2	P29354	891
S100A8	TAOK1	Q7L7X3	888
S100A8	CD44	P16070	879
S100A8	TP53BP2	Q13625	835
S100A8	TLR4	O00206	779
S100A8	SMAD3	P84022	748
S100A8	CXCL8	P10145	731
S100A8	S100A6	P06703	689
S100A8	ITGB1	P05556	663
S100A8	NOD1	Q9Y239	662

IntAct

159 interactions, top by confidence:

A	B	Type	Score
S100A9	S100A8	psi-mi:“MI:0914”(association)	0.750
S100A8	S100A9	psi-mi:“MI:0915”(physical association)	0.750
SHC1	AP2A1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
UBASH3B	EGFR	psi-mi:“MI:0914”(association)	0.690
GAPDH	S100A8	psi-mi:“MI:0914”(association)	0.650
S100A8	GAPDH	psi-mi:“MI:0914”(association)	0.650
S100A8	GAPDH	psi-mi:“MI:0407”(direct interaction)	0.650
GAPDH	S100A8	psi-mi:“MI:0407”(direct interaction)	0.650
TRPM4	S100A8	psi-mi:“MI:0407”(direct interaction)	0.540
S100A8	TRPM4	psi-mi:“MI:0915”(physical association)	0.540
KSR2	POLR3A	psi-mi:“MI:0914”(association)	0.530
TBC1D22B	A2ML1	psi-mi:“MI:0914”(association)	0.530
SLC15A4	PGRMC1	psi-mi:“MI:0914”(association)	0.530
RYK	PCDH7	psi-mi:“MI:0914”(association)	0.530
NOS2	GAPDH	psi-mi:“MI:0914”(association)	0.500
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
CFTR	CNOT1	psi-mi:“MI:0914”(association)	0.480
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
NOS2	S100A8	psi-mi:“MI:0914”(association)	0.460

BioGRID (240): NCF2 (Reconstituted Complex), S100A8 (Affinity Capture-MS), S100A8 (Reconstituted Complex), S100A8 (Affinity Capture-MS), S100A8 (Affinity Capture-MS), S100A8 (Affinity Capture-MS), S100A8 (Affinity Capture-MS), S100A8 (Affinity Capture-MS), S100A9 (Reconstituted Complex), S100A8 (Reconstituted Complex), S100A8 (Reconstituted Complex), SMTNL2 (Affinity Capture-MS), S100A8 (Affinity Capture-MS), DPH6 (Affinity Capture-MS), EFHD1 (Affinity Capture-MS)

ESM2 similar proteins: A5PJN0, A7K6Y8, A7K6Y9, F1SSF9, O73763, O76038, O77791, P05109, P06702, P27005, P28318, P28782, P31725, P33763, P43367, P45961, P50115, P50116, P50117, P63083, P63084, P79105, P80511, Q01449, Q06A97, Q0VFG3, Q14ST5, Q28050, Q3MHP3, Q4R6C5, Q5E9G1, Q5SY68, Q5XJX1, Q63ZJ3, Q6AXZ3, Q6DJ05, Q6R556, Q6S5I3, Q75KU4, Q803V3

Diamond homologs: A7K6Y8, A7K6Y9, O77691, O77791, P02632, P02633, P02634, P02638, P02639, P04271, P04631, P05109, P05942, P05943, P05964, P06702, P06703, P07091, P14069, P20930, P22793, P23297, P24479, P24480, P25815, P27004, P27005, P28318, P28782, P28783, P29377, P30801, P31725, P31949, P31950, P33763, P35467, P50114, P50115, P50116

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
S100A8	“up-regulates activity”	AGER	binding
S100A8	“down-regulates activity”	TLR4	binding
calcium(2+)	“up-regulates activity”	S100A8	“chemical activation”
S100A8	“up-regulates quantity by stabilization”	Tubulin	binding
hsa-mir-24-3p	“down-regulates quantity by repression”	S100A8	“post transcriptional regulation”
S100A8	“form complex”	“Calprotectin complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 173 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of canonical Wnt signaling pathway	10	10.4×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

5 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

190 predictions. Top by Δscore:

Variant	Effect	Δscore
1:153390389:CCTCA:C	donor_loss	1.0000
1:153390390:CTCAC:C	donor_loss	1.0000
1:153390391:TCA:T	donor_loss	1.0000
1:153390392:CACCC:C	donor_loss	1.0000
1:153390393:AC:A	donor_gain	1.0000
1:153390394:C:CT	donor_loss	1.0000
1:153390394:CC:C	donor_gain	1.0000
1:153390403:A:AC	donor_gain	1.0000
1:153390404:C:CC	donor_gain	1.0000
1:153390253:T:C	acceptor_gain	0.9900
1:153390253:T:TC	acceptor_gain	0.9900
1:153390393:A:AC	donor_gain	0.9900
1:153390394:C:CC	donor_gain	0.9900
1:153390442:C:A	donor_gain	0.9900
1:153390856:CCCA:C	donor_gain	0.9900
1:153390244:C:CC	acceptor_gain	0.9800
1:153390555:CAC:C	acceptor_gain	0.9800
1:153390556:ACC:A	acceptor_loss	0.9800
1:153390558:C:A	acceptor_loss	0.9800
1:153390559:T:G	acceptor_loss	0.9800
1:153390240:TTTT:T	acceptor_gain	0.9700
1:153390249:A:T	acceptor_gain	0.9700
1:153390553:CCCAC:C	acceptor_gain	0.9700
1:153390554:CCACC:C	acceptor_gain	0.9700
1:153390560:GAAAA:G	acceptor_loss	0.9700
1:153390561:AAAAA:A	acceptor_loss	0.9700
1:153390883:T:A	donor_gain	0.9700
1:153390939:C:A	donor_gain	0.9700
1:153390239:TTTTT:T	acceptor_gain	0.9600
1:153390241:TTT:T	acceptor_gain	0.9600

AlphaMissense

626 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:153390172:G:C	F71L	0.980
1:153390172:G:T	F71L	0.980
1:153390174:A:G	F71L	0.980
1:153390435:A:G	L34P	0.979
1:153390188:A:T	V66D	0.970
1:153390490:A:C	Y16D	0.969
1:153390477:G:A	S20F	0.967
1:153390150:C:G	G79R	0.965
1:153390454:C:G	A28P	0.964
1:153390176:T:A	E70V	0.961
1:153390426:A:G	L37S	0.959
1:153390478:A:G	S20P	0.958
1:153390141:C:G	A82P	0.957
1:153390450:A:T	V29D	0.957
1:153390182:A:G	F68S	0.956
1:153390181:G:C	F68L	0.955
1:153390181:G:T	F68L	0.955
1:153390183:A:G	F68L	0.955
1:153390173:A:G	F71S	0.954
1:153390208:A:C	D59E	0.953
1:153390208:A:T	D59E	0.953
1:153390210:C:G	D59H	0.949
1:153390170:A:G	L72P	0.941
1:153390412:A:G	C42R	0.939
1:153390514:C:G	A8P	0.938
1:153390175:C:A	E70D	0.937
1:153390175:C:G	E70D	0.937
1:153390192:C:G	A65P	0.936
1:153390220:G:C	F55L	0.936
1:153390220:G:T	F55L	0.936

dbSNP variants (sampled 300 via entrez): RS1000277856 (1:153402358 G>T), RS1000278785 (1:153415717 G>A,C,T), RS1000322639 (1:153401082 T>C), RS1000325715 (1:153391146 G>A,C), RS1000353643 (1:153415604 G>T), RS1000411134 (1:153396298 G>C,T), RS1000564606 (1:153410084 G>A), RS1000583329 (1:153415123 G>A), RS1000631030 (1:153411139 G>T), RS1000655789 (1:153401334 C>T), RS1000694675 (1:153414646 CTCAT>C), RS1000752420 (1:153397448 G>A), RS1000929700 (1:153392570 G>C,T), RS1000932012 (1:153410292 G>A), RS1000940933 (1:153423200 A>G)

Disease associations

OMIM: gene MIM:123885 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005187_1	Matrix metalloproteinase-8 levels	5.000000e-13
GCST008916_87	Asthma	2.000000e-13
GCST90002393_50	Monocyte count	3.000000e-18

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005091	monocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725128 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.00	IC50	1e+04	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178875: Inhibition of S100A8 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	10.0000	uM

CTD chemical–gene interactions

114 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	7
Arsenic Trioxide	decreases expression, increases expression, increases sumoylation, decreases response to substance, affects cotreatment	7
Tobacco Smoke Pollution	decreases expression, increases expression, affects expression	7
Tretinoin	affects cotreatment, increases expression, decreases reaction, decreases expression	6
Tetrachlorodibenzodioxin	decreases reaction, increases expression, affects cotreatment	5
perfluorooctane sulfonic acid	decreases expression	4
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression, increases expression	4
Calcitriol	decreases expression, increases expression	4
Aflatoxin B1	affects expression, increases expression, increases methylation	4
Particulate Matter	increases abundance, increases expression, affects expression, decreases expression, affects cotreatment	4
Air Pollutants	increases expression, affects expression, decreases expression, increases abundance	3
Estradiol	increases expression, decreases expression, affects cotreatment	3
Valproic Acid	affects cotreatment, decreases expression, increases expression	3
perfluoro-n-nonanoic acid	decreases expression	2
monomethylarsonous acid	affects expression, increases expression	2
Pioglitazone	decreases expression, increases expression	2
Diethylhexyl Phthalate	affects cotreatment, increases expression	2
Nickel	increases expression	2
Ozone	increases expression	2
Phenobarbital	affects expression, increases expression	2
beta-Naphthoflavone	increases expression	2
2,2’,3,4’,5,5’,6-heptachlorobiphenyl	decreases expression	1
bisphenol F	decreases expression	1
shuanghuang shengbai	decreases expression	1
Asian ginseng	affects cotreatment, increases expression	1
4-oxoretinoic acid	increases expression	1
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
tetrachloroisophthalonitrile	increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697605	Binding	Inhibition of S100A8 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2EI	Abcam HeLa S100A8 KO	Cancer cell line	Female
CVCL_B8P4	Abcam HCT 116 S100A8 KO	Cancer cell line	Male
CVCL_B9RG	Abcam A-549 S100A8 KO	Cancer cell line	Male
CVCL_C0A1	Abcam THP-1 S100A8 KO	Cancer cell line	Male
CVCL_D2H8	Abcam MCF-7 S100A8 KO	Cancer cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.