Histatin‐1, a histidine‐rich peptide in human saliva, promotes cell‐substrate and cell‐cell adhesion

Histatins (Hsts) are histidine‐rich peptides exclusively present in the saliva of higher primates. In this study, we explored the effects of Hsts on cell‐substrate and cell‐cell adhesion. Histatin (Hst)‐1 caused a significant (>2‐fold) increase (EC50 = 1 μM) in the ability of human adherent cells to attach and spread, even in conditions that impaired cell spreading. Other tested Hsts did not stimulate cell spreading, indicating a specific effect of Hst1. The effect of Hst1 on cell‐cell adhesion was investigated by using transepithelial resistance (TER) measurements in the human cell line Caco‐2, a widely used model for the epithelial layer. We found that 10 μM Hst1 caused a 20% increase in TER compared to the negative control, indicating a function for Hst1 in intercellular cell adhesion and epithelial integrity. A role for Hst1 in both cell‐substrate and cell‐cell adhesion is highly conceivable, because these 2 modes of adhesion are closely related via shared components and connected signaling pathways.—Van Dijk, I. A., Nazmi, K., Bolscher, J. G. M., Veerman, E. C. I., Stap, J. Histatin‐1, a histidine‐rich peptide in human saliva, promotes cell‐substrate and cell‐cell adhesion. FASEB J. 29, 3124‐3132 (2015). www.fasebj.org

[1]  E. Veerman,et al.  Human antimicrobial peptide histatin 5 is a cell‐ penetrating peptide targeting mitochondrial ATP synthesis in Leishmania , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  Dorthea A. Johnson,et al.  Effect of donor age on the concentrations of histatins in human parotid and submandibular/sublingual saliva. , 2000, Archives of oral biology.

[3]  Integrins and cadherins join forces to form adhesive networks , 2011, Journal of Cell Science.

[4]  Thomas J. Raub,et al.  Characterization of the human colon carcinoma cell line (Caco-2) as a model system for intestinal epithelial permeability. , 1989, Gastroenterology.

[5]  V. Iacono,et al.  Fungistatic and fungicidal activity of human parotid salivary histidine-rich polypeptides on Candida albicans , 1984, Infection and immunity.

[6]  H. Gralnick,et al.  Novel function for beta 1 integrins in keratinocyte cell-cell interactions , 1990, The Journal of cell biology.

[7]  E. Veerman,et al.  Histatins are the major wound‐closure stimulating factors in human saliva as identified in a cell culture assay , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[8]  M. Avolio,et al.  E-cadherin endocytosis regulates the activity of Rap1: a traffic light GTPase at the crossroads between cadherin and integrin function , 2005, Journal of Cell Science.

[9]  J. Steele,et al.  Role of serum vitronectin and fibronectin in adhesion of fibroblasts following seeding onto tissue culture polystyrene. , 1992, Journal of biomedical materials research.

[10]  S. Gibbs,et al.  Structure‐activity analysis of histatin, a potent wound healing peptide from human saliva: cyclization of histatin potentiates molar activity 1000‐fold , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[11]  E. Azen,et al.  Histatins, a family of salivary histidine-rich proteins, are encoded by at least two loci (HIS1 and HIS2). , 1989, Biochemical and biophysical research communications.

[12]  S. Levitz,et al.  Histatins, a novel family of histidine-rich proteins in human parotid secretion. Isolation, characterization, primary structure, and fungistatic effects on Candida albicans. , 1988, The Journal of biological chemistry.

[13]  V. Iacono,et al.  Growth-inhibitory and bactericidal effects of human parotid salivary histidine-rich polypeptides on Streptococcus mutans , 1984, Infection and immunity.

[14]  P. Wong,et al.  Interaction of tannin with human salivary histatins. , 1999, Journal of agricultural and food chemistry.

[15]  R. Presland,et al.  Epithelial structural proteins of the skin and oral cavity: function in health and disease. , 2000, Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists.

[16]  Carla P. Guimarães,et al.  Sortase A as a tool for high‐yield histatin cyclization , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[17]  B. Gumbiner,et al.  Cell Adhesion: The Molecular Basis of Tissue Architecture and Morphogenesis , 1996, Cell.

[18]  D. Whittaker,et al.  Oral development and histology , 1988 .

[19]  R. Conradi,et al.  Caco-2 Cell Monolayers as a Model for Drug Transport Across the Intestinal Mucosa , 1990, Pharmaceutical Research.

[20]  R. Steigbigel,et al.  Pilot study comparing the salivary cationic protein concentrations in healthy adults and AIDS patients: correlation with antifungal activity. , 1992, Journal of acquired immune deficiency syndromes.

[21]  B. Gumbiner,et al.  Crosstalk between different adhesion molecules. , 2006, Current opinion in cell biology.

[22]  F. Oppenheim,et al.  Kinetics of histatin proteolysis in whole saliva and the effect on bioactive domains with metal‐binding, antifungal, and wound‐healing properties , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[23]  Seungho Wang,et al.  Effects of hyperthermia on the cytoskeleton and focal adhesion proteins in a human thyroid carcinoma cell line , 1999, Journal of cellular biochemistry.

[24]  H. Larjava,et al.  Epithelial Integrins with Special Reference to Oral Epithelia , 2011, Journal of dental research.

[25]  D. Gradl,et al.  Cross-regulation of Wnt signaling and cell adhesion. , 2004, Differentiation; research in biological diversity.

[26]  Karla Müller,et al.  Single cell viability and impact of heating by laser absorption , 2011, European Biophysics Journal.

[27]  D. Relman,et al.  An ecological and evolutionary perspective on human–microbe mutualism and disease , 2007, Nature.

[28]  R. Juliano,et al.  Integrin Signaling , 2005, Cancer and Metastasis Reviews.

[29]  M. Finn,et al.  "Clickable" agarose for affinity chromatography. , 2005, Bioconjugate chemistry.

[30]  F. Oppenheim,et al.  Molecular cloning of human submandibular histatins. , 1990, Archives of oral biology.

[31]  C. O'neill,et al.  Anchorage and growth regulation in normal and virus‐transformed cells , 1968, International journal of cancer.

[32]  H. Wyandt,et al.  Localization of the genes for histatins to human chromosome 4q13 and tissue distribution of the mRNAs. , 1989, American journal of human genetics.

[33]  A. Marchiando,et al.  Epithelial barriers in homeostasis and disease. , 2010, Annual review of pathology.

[34]  J. Bosch,et al.  Concentration and fate of histatins and acidic proline-rich proteins in the oral environment. , 2009, Archives of oral biology.

[35]  J. J. Pollock,et al.  Histatins 2 and 4 are autoproteolytic degradation products of human parotid saliva. , 1992, Oral microbiology and immunology.

[36]  A. Bennick,et al.  Identification of histatins as tannin-binding proteins in human saliva. , 1995, The Biochemical journal.

[37]  E. Veerman,et al.  Synthetic histatin analogues with broad-spectrum antimicrobial activity. , 1997, The Biochemical journal.

[38]  L. Hjelmeland,et al.  ARPE-19, a human retinal pigment epithelial cell line with differentiated properties. , 1996, Experimental eye research.