Histatins are cationic and histidine-rich peptides mainly found in the saliva of higher primates . They 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, Hst 2/HTN1 and Hst 3/HTN3) .
Histatin 3 (Hst 3) is mostly involved in cell migration and wound healing in the oral cavity . Also stimulates cell proliferation after binding to heat shock protein HSC70, which enhances HSC70-CDKN1B complex formation and subsequent ubiquitination during G1/S transition . Also displays antifungal activity against pathogenic yeast Candida albicans, however with less effectiveness than Hst 5 (, ).
Histatin 5 (Hst 5), a fragment of Hst 3, is the major histatin exhibiting antifungal and antibacterial activities (   , ). It is effective against pathogenic yeast C. albicans, C. neoformans, C. glabrata and S. cerevisiae as well as ESKAPE bacterial pathogens (  ). Secreted Hst 5 mediates a multi-step intracellular mechanism of action against the pathogen. Depending on peptide concentration and pathogen, uptake across the membrane can occur through transporters, direct interaction with plasma membrane and/or receptor-mediated endocytosis ( ). Binds C. albicans cell wall proteins SSA1 and SSA2 and glycans in an energy-independent manner, then is taken up by the cells through fungal polyamine transporters DUR3 and DUR31 in an energy-dependent manner ( , ). Internalized Hst5 is then targeted to the energized mitochondrion to induce reactive oxygen species (ROS) formation and subsequent release of intracellular non-lytic ATP which ultimately leads to fungal cell death ( ). In addition, inhibits C. albicans TRK1 potassium-transporter which causes exudation of intracellular K(+), generating an osmotic imbalance leading to delayed membrane lysis and cell death . Also acts as a potent inhibitor of bacterial proteases such as Lys-gingipain and Arg-gingipain (rgpB) from P. gingivalis as well as human metalloproteases MMP2 and MMP9 . The binding of metals such as zinc, copper or nickel with Hst 5 results in the protection of the enamel and antimicrobial activities such as the inhibition of microbial growth by decreasing the metal concentration, the formation of ROS commonly associated with redox-active metals, the induction of membrane disruption mediated by zinc binding ( , ). Also involved in coating oral surfaces in the form of a salivary film which reduces colonization by C. albicans on epithelial cell surfaces . Secreted Hst 5 can also internalize mammalian epithelial cells and target the mitochondria although it does not exert cytotoxic effects in these cells . In contrast with Hst 3, not able to promote wound healing in mammalian host cells .
Subcellular locations: Secreted
Secreted by serous acinar and demilune cells.
Subcellular locations: Secreted, Mitochondrion
Targeted to mitochondria in pathogen cells after internalization . Also localized in the vacuole in pathogen cells . Also co-localized with mitochondria after internalization in host mammalian cells .