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 been not 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 .
Subcellular locations: Secreted, Mitochondrion, Endoplasmic reticulum membrane
Hst 1 co-localized with mitochondria as well as the endoplasmic reticulum (ER) after internalization in host cells.
Subcellular locations: Secreted, Mitochondrion, Endoplasmic reticulum membrane
Hst 2 co-localized with mitochondria as well as the endoplasmic reticulum (ER) after internalization in host cells.
Submandibular and parotid glands.