HTN1

Summary

HTN1 (histatin 1, HGNC:5283) is a protein-coding gene on chromosome 4q13.3, encoding Histatin-1 (P15515). Histatins (Hsts) are cationic and histidine-rich secreted peptides mainly synthesized by saliva glands of humans and higher primates.

This gene encodes a member of the histatin family of small, histidine-rich, cationic proteins. They function as antimicrobial peptides and are important components of the innate immune system. Histatins are found in saliva and exhibit antibacterial, antifungal activities and function in wound healing.

Source: NCBI Gene 3346 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 7 total
• MANE Select transcript: NM_002159

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5283
Approved symbol	HTN1
Name	histatin 1
Location	4q13.3
Locus type	gene with protein product
Status	Approved
Aliases	HIS1
Ensembl gene	ENSG00000126550
Ensembl biotype	protein_coding
OMIM	142701
Entrez	3346

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 retained_intron

ENST00000246896, ENST00000503645, ENST00000506754, ENST00000511674

RefSeq mRNA: 2 — MANE Select: NM_002159 NM_001368990, NM_002159

CCDS: CCDS3534

Canonical transcript exons

ENST00000246896 — 6 exons

Exon	Start	End
ENSE00000865225	70055498	70055602
ENSE00001024603	70054322	70054342
ENSE00001171130	70058580	70058848
ENSE00002449602	70054421	70054450
ENSE00002483922	70050438	70050495
ENSE00003576458	70053064	70053127

Expression profiles

Bgee: expression breadth broad, 41 present calls, max score 77.17.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 135.7463 / max 110055.0515, expressed in 30 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47873	117.2553	27
47874	18.1819	11
47876	0.1972	4
47875	0.1119	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.17	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	71.51	gold quality
saliva-secreting gland	UBERON:0001044	69.98	gold quality
minor salivary gland	UBERON:0001830	67.04	gold quality
placenta	UBERON:0001987	65.41	gold quality
tonsil	UBERON:0002372	63.01	gold quality
bone marrow	UBERON:0002371	52.24	gold quality
skeletal muscle tissue	UBERON:0001134	44.00	gold quality
colonic epithelium	UBERON:0000397	41.46	gold quality
sural nerve	UBERON:0015488	40.72	gold quality
muscle tissue	UBERON:0002385	40.18	gold quality
urinary bladder	UBERON:0001255	40.00	gold quality
stromal cell of endometrium	CL:0002255	38.60	gold quality
monocyte	CL:0000576	37.61	gold quality
ganglionic eminence	UBERON:0004023	37.15	gold quality
blood	UBERON:0000178	36.86	gold quality
duodenum	UBERON:0002114	36.76	gold quality
leukocyte	CL:0000738	36.71	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
hindlimb stylopod muscle	UBERON:0004252	35.41	gold quality
apex of heart	UBERON:0002098	35.28	gold quality
adrenal tissue	UBERON:0018303	35.08	gold quality
right adrenal gland cortex	UBERON:0035827	33.96	silver quality
left adrenal gland cortex	UBERON:0035825	33.84	silver quality
adrenal gland	UBERON:0002369	33.17	gold quality
primary visual cortex	UBERON:0002436	32.89	gold quality
prefrontal cortex	UBERON:0000451	32.65	gold quality
pancreas	UBERON:0001264	32.49	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.12

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 16)

• inhibits calcium phosphate precipitation (PMID:12060866)
• The results allowed locating sulfation on the last four tyrosines (Tyr 27, 30, 34, and 36). (PMID:17503797)
• histatin 1 (Hst1) and histatin 2 (Hst2) as major wound-closing factors in human saliva (PMID:18650243)
• These findings indicate that the regulation of the histatin gene expression may be intricate, and it seems to have a cell-type preference in the salivary gland cells. (PMID:19060311)
• We investigated interactions among and functions of histatin 1 and the other proteins that are present in saliva by using high-throughput mass spectrometric techniques. This led to the identification of 43 proteins able to interact with histatin 1. (PMID:23001880)
• Histatins are salivary proteins with antimicrobial activity. (PMID:2303595)
• Histatin-1 is specifically expressed in human lacrimal epithelium. (PMID:26824896)
• This study evaluated the effects of Hst1 on cellular barrier function. Hst1 counteracted the effects of epithelial-mesenchymal transition inducers on the outgrowth of oral cancer cell spheroids, suggesting that Hst1 affects processes that are implicated in cancer progression. (PMID:28522595)
• salivary histatin-1 is a novel proangiogenic factor that may contribute to oral wound healing (PMID:28751526)
• Histatin 1 is one of the most abundant histatins and recent reports show that it has a stimulating effect on cellular adherence, thereby suggesting a role in maintaining the quality of the epithelial barrier and stimulating mesenchymal-to-epithelial transition. (PMID:30138105)
• Presence of Histatin-1 in Human Tears and Association with Aqueous Deficient Dry Eye Diagnosis: A Preliminary Study. (PMID:31311993)
• Salivary Histatin 1 and 2 Are Targeted to Mitochondria and Endoplasmic Reticulum in Human Cells. (PMID:32225006)
• Human salivary histatin-1 (Hst1) promotes bone morphogenetic protein 2 (BMP2)-induced osteogenesis and angiogenesis. (PMID:32484586)
• Histatin-1 is an endogenous ligand of the sigma-2 receptor. (PMID:34233061)
• Association Between PD-L1 and Histatin1, 3 Expression in Advanced Head and Neck Squamous Cell Carcinoma. (PMID:35489730)
• GPCR/endocytosis/ERK signaling/S2R is involved in the regulation of the internalization, mitochondria-targeting and -activating properties of human salivary histatin 1. (PMID:35970844)

Cross-species orthologs

0 orthologs

Paralogs (2): STATH (ENSG00000126549), HTN3 (ENSG00000205649)

Protein

Protein identifiers

Histatin-1 — P15515 (reviewed: P15515)

Alternative names: Histidine-rich protein 1, Post-PB protein

All UniProt accessions (1): P15515

UniProt curated annotations — full annotation on UniProt →

Function. Histatins (Hsts) are cationic and histidine-rich secreted peptides mainly synthesized by saliva glands of humans and higher primates. Hsts are considered to be major precursors of the protective proteinaceous structure on tooth surfaces (enamel pellicle). Hsts can be divided into two major groups according to their biological functions: antimicrobial Hsts (e.g. Hst 5/HTN3) and cell-activating Hsts (e.g. Hst 1/HTN1 and Hst 2/HTN1). Hst 1/HTN1 and Hst 2/HTN1 act in different cell types (epithelium, fibroblasts and endothelium) in oral and non-oral mucosa. Hst 1 functions primarily as a wound healing factor by activating cell-surface and cell-cell adhesions, cell spreading and migration and it can also stimulate cellular metabolic activity. Hst 1 is internalized in host cells in a stereospecific and energy-dependent process, which is partially mediated by the G protein-coupled receptors (GPCR)-activated endocytosis. Internalized Hst 1 is targeted and released via early endosomes trafficking to the mitochondria, where it significantly enhances mitochondrial energy metabolism. At the mitochondria, Hst 1 increases mitochondria-ER contacts through binding with ER receptor TMEM97, which also stimulates metabolic activity and cell migration and may as well regulate calcium homeostasis of the cell. Also activates the ERK1/2 signaling pathway to promote cell migration, possibly upon interaction with GPRCs at the plasma membrane. Also triggers the RIN2/Rab5/Rac1 signaling cascade which activates endothelial cell adhesion, spreading and migration required for angiogenesis in the oral wound healing process, however the receptor that transduces Hst 1 signal has not yet been identified. Also displays antimicrobial functions against pathogenic yeast Candida albicans, although with less effectiveness than Hst 5. Hst 2 consists of the fragment sequence 12-28 of Hst 1. Similar to Hst 1, actively and stereospecifically internalized in host cells and targeted to the mitochondria and the ER and promotes cell metabolic activity. Also activates the ERK1/2 signaling pathway to promote cell migration and wound closure. In contrast with Hst 1, not able to promote cell-substrate and cell-cell adhesion.

Subunit / interactions. Interacts with TMEM97; the interaction induces Hst1-stimulating wound healing.

Subcellular location. Secreted. Mitochondrion. Endoplasmic reticulum membrane Secreted. Endoplasmic reticulum membrane.

Tissue specificity. Submandibular and parotid glands.

Post-translational modifications. Phosphorylated.

Domain organisation. The wound healing domain in C-terminus may promote cell migration and proliferation.

Miscellaneous. The recommended nomenclature of salivary peptides follows published guidelines. In agreement with the authors, it has been decided to indicate the boundaries of the peptides according to the positions within the precursor, and not in the mature protein, as has formerly been proposed. Histatin 1, histatin 3 and histatin 5 constitute more than 80% of the total histatin concentration.

Similarity. Belongs to the histatin/statherin family.

RefSeq proteins (2): NP_001355919, NP_002150* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR030773	Histatin/statherin	Family

UniProt features (9 total): modified residue 5, peptide 2, signal peptide 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15515-F1	62.18	0.07

Functional residue map

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

Post-translational modifications (5): 21, 46, 49, 53, 55

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6803157	Antimicrobial peptides

MSigDB gene sets: 155 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, FXR_IR1_Q6, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, MYOGENIN_Q6, WWTAAGGC_UNKNOWN, GOBP_REGULATION_OF_WOUND_HEALING, TGCGCANK_UNKNOWN, GAANYNYGACNY_UNKNOWN, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, FOXO1_01, GOBP_POSITIVE_REGULATION_OF_SUBSTRATE_ADHESION_DEPENDENT_CELL_SPREADING, FOXD3_01, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION

GO Biological Process (10): positive regulation of metabolic process (GO:0009893), positive regulation of cell-cell adhesion (GO:0022409), biomineral tissue development (GO:0031214), killing of cells of another organism (GO:0031640), positive regulation of vascular wound healing (GO:0035470), defense response to bacterium (GO:0042742), defense response to fungus (GO:0050832), positive regulation of wound healing (GO:0090303), positive regulation of substrate adhesion-dependent cell spreading (GO:1900026), positive regulation of wound healing, spreading of epidermal cells (GO:1903691)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of wound healing	2
defense response	2
cellular anatomical structure	2
cytoplasm	2
intracellular membrane-bounded organelle	2
metabolic process	1
regulation of metabolic process	1
positive regulation of cellular process	1
regulation of cell-cell adhesion	1
positive regulation of cell adhesion	1
cell-cell adhesion	1
tissue development	1
animal organ development	1
cell killing	1
disruption of cell in another organism	1
positive regulation of angiogenesis	1
vascular wound healing	1
regulation of vascular wound healing	1
response to bacterium	1
response to fungus	1
wound healing	1
regulation of wound healing	1
positive regulation of response to wounding	1
positive regulation of cell-substrate adhesion	1
substrate adhesion-dependent cell spreading	1
regulation of substrate adhesion-dependent cell spreading	1
positive regulation of cell migration	1
wound healing, spreading of epidermal cells	1
regulation of wound healing, spreading of epidermal cells	1
binding	1
endomembrane system	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Protein interactions and networks

STRING

374 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HTN1	STATH	P02808	991
HTN1	MUC7	Q8TAX7	919
HTN1	MUC5B	Q9HC84	851
HTN1	PDGFRB	P09619	757
HTN1	CST4	P01036	737
HTN1	ALB	P02768	583
HTN1	PRPF3	O43395	538
HTN1	LTF	P02788	526
HTN1	SMR3B	P02814	501
HTN1	CAMP	P49913	480
HTN1	PRR4	Q16378	442
HTN1	PNRC1	Q12796	437
HTN1	CSN1S1	P47710	433
HTN1	TMEM186	Q96B77	432
HTN1	MUC1	P13931	432

IntAct

4 interactions, top by confidence:

A	B	Type	Score
HTN1	MUC7	psi-mi:“MI:0915”(physical association)	0.510
GPR107	JTB	psi-mi:“MI:0914”(association)	0.350

BioGRID (7): HTN1 (Affinity Capture-MS), HTN1 (Co-purification), HTN1 (Affinity Capture-MS), HTN1 (Affinity Capture-MS), HTN1 (Co-fractionation), HTN1 (Co-fractionation), HTN1 (Proximity Label-MS)

ESM2 similar proteins: A0A0N7FMT9, A8Y3N1, B3SVF0, C5J897, C6KGD8, G1FE62, H2A0M6, H2A0N0, H2A0P1, O08633, O52055, P02808, P07185, P08825, P08826, P08827, P08828, P08829, P0C0U2, P0C0U3, P0DME3, P0DMF8, P13424, P13425, P13426, P13531, P15515, P27781, P34300, P34301, P34407, P34625, P43513, P43514, P43516, P43517, P50438, P50602, P83360, P86960

Diamond homologs: P02808, P15515, P15516, P34084

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	5
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

562 predictions. Top by Δscore:

Variant	Effect	Δscore
4:70053058:TTATA:T	acceptor_loss	1.0000
4:70053059:TATA:T	acceptor_loss	1.0000
4:70053061:TA:T	acceptor_loss	1.0000
4:70053062:A:AG	acceptor_gain	1.0000
4:70053062:A:T	acceptor_loss	1.0000
4:70053063:G:A	acceptor_loss	1.0000
4:70053063:G:GG	acceptor_gain	1.0000
4:70053124:GATT:G	donor_gain	1.0000
4:70053125:ATT:A	donor_gain	1.0000
4:70053126:TT:T	donor_gain	1.0000
4:70053128:G:GG	donor_gain	1.0000
4:70054451:G:GG	donor_gain	1.0000
4:70050491:AAAAG:A	donor_loss	0.9900
4:70050492:AAAG:A	donor_gain	0.9900
4:70050493:AAGGT:A	donor_loss	0.9900
4:70050494:AGGTA:A	donor_loss	0.9900
4:70050495:GGT:G	donor_loss	0.9900
4:70050496:G:GA	donor_loss	0.9900
4:70050497:T:A	donor_loss	0.9900
4:70053060:ATAG:A	acceptor_gain	0.9900
4:70053062:AG:A	acceptor_gain	0.9900
4:70053063:GG:G	acceptor_gain	0.9900
4:70053123:TGATT:T	donor_gain	0.9900
4:70053124:GATTG:G	donor_gain	0.9900
4:70053127:TGTA:T	donor_loss	0.9900
4:70053128:GTAAG:G	donor_loss	0.9900
4:70053129:T:A	donor_loss	0.9900
4:70053130:A:AG	donor_loss	0.9900
4:70053131:A:AT	donor_loss	0.9900
4:70053132:G:T	donor_loss	0.9900

AlphaMissense

378 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:70053096:C:A	A7D	0.911
4:70053108:C:A	A11D	0.866
4:70053111:T:C	L12P	0.832
4:70053111:T:A	L12H	0.812
4:70053102:T:A	V9D	0.807
4:70055522:T:C	F43L	0.806
4:70055524:T:A	F43L	0.806
4:70055524:T:G	F43L	0.806
4:70053111:T:G	L12R	0.801
4:70053090:T:A	V5D	0.785
4:70054445:T:C	F33L	0.776
4:70054447:C:A	F33L	0.776
4:70054447:C:G	F33L	0.776
4:70053092:T:C	F6L	0.770
4:70053094:T:A	F6L	0.770
4:70053094:T:G	F6L	0.770
4:70053114:T:G	M13R	0.717
4:70053114:T:A	M13K	0.712
4:70053083:T:C	F3L	0.704
4:70053085:T:A	F3L	0.704
4:70053085:T:G	F3L	0.704
4:70053124:G:A	M16I	0.674
4:70053124:G:C	M16I	0.674
4:70053124:G:T	M16I	0.674
4:70053107:G:C	A11P	0.653
4:70053082:G:C	K2N	0.613
4:70053082:G:T	K2N	0.613
4:70053095:G:C	A7P	0.591

dbSNP variants (sampled 300 via entrez): RS1000850181 (4:70057930 A>G), RS1000850574 (4:70051957 T>C), RS10008606 (4:70054491 C>A,T), RS1001970723 (4:70049506 T>C), RS10019826 (4:70056347 G>A,T), RS1002022932 (4:70049239 A>G), RS1002679540 (4:70051677 A>G,T), RS1002785803 (4:70057226 G>A), RS1003035460 (4:70051885 T>C), RS1003634044 (4:70050761 T>A,C), RS1003790797 (4:70055927 C>A,T), RS1003843177 (4:70058343 G>T), RS1004845592 (4:70056850 C>G,T), RS1005829988 (4:70048938 A>G), RS1005882498 (4:70048677 T>A)

Disease associations

OMIM: gene MIM:142701 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006904_12	Cerebral amyloid deposition (PET imaging)	6.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007707	cerebral amyloid deposition measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression	1
Mercury	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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