Psoriasin (S100A7) is a principal antimicrobial peptide of the human tongue

Meyer, Jan; Harder, Jürgen; Sipos, Bence; Maune, Steffen; Klöppel, G.; Bartels, John; Jm, Schröder; Gläser, Regine

doi:10.1038/mi.2008.3

Cited by 44 publications

(47 citation statements)

References 26 publications

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“…oxS100A7 is highly abundant on healthy human skin and several mucosal surfaces (11)(12)(13). Its antibacterial activity is Zn 2+ -sensitive, acting via a histidinecoordinated low-affinity Zn 2+ -binding site (14).…”

Section: Significancementioning

confidence: 99%

Disulphide-reduced psoriasin is a human apoptosis-inducing broad-spectrum fungicide

Hein

Takahashi

Tsumori

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The unexpected resistance of psoriasis lesions to fungal infections suggests local production of an antifungal factor. We purified Trichophyton rubrum-inhibiting activity from lesional psoriasis scale extracts and identified the Cys-reduced form of S100A7/psoriasin (redS100A7) as a principal antifungal factor. redS100A7 inhibits various filamentous fungi, including the mold Aspergillus fumigatus, but not Candida albicans. Antifungal activity was inhibited by Zn 2+, suggesting that redS100A7 interferes with fungal zinc homeostasis. Because S100A7-mutants lacking a single cysteine are no longer antifungals, we hypothesized that redS100A7 is acting as a Zn 2+ -chelator. Immunogold electron microscopy studies revealed that it penetrates fungal cells, implicating possible intracellular actions. In support with our hypothesis, the cell-penetrating Zn 2+ -chelator TPEN was found to function as a broad-spectrum antifungal. Ultrastructural analyses of redS100A7-treated T. rubrum revealed marked signs of apoptosis, suggesting that its mode of action is induction of programmed cell death. TUNEL, SYTOX-green analyses, and caspase-inhibition studies supported this for both T. rubrum and A. fumigatus. Whereas redS100A7 can be generated from oxidized S100A7 by action of thioredoxin or glutathione, elevated redS100A7 levels in fungal skin infection indicate induction of both S100A7 and its reducing agent in vivo. To investigate whether redS100A7 and TPEN are antifungals in vivo, we used a guinea pig tinea pedes model for fungal skin infections and a lethal mouse Aspergillus infection model for lung infection and found antifungal activity in both in vivo animal systems. Thus, selective fungal cellpenetrating Zn 2+ -chelators could be useful as an urgently needed novel antifungal therapeutic, which induces programmed cell death in numerous fungi.antifungal | innate immunity | epithelial defense | psoriasin | S100A7

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Section: Significancementioning

confidence: 99%

Disulphide-reduced psoriasin is a human apoptosis-inducing broad-spectrum fungicide

Hein

Takahashi

Tsumori

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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“…6,8,9 S100A7 is recognized as an antimicrobial factor of the skin as well as the human tongue, esophagus and female genital tract. 10–13 Several mechanisms for the antimicrobial activity of S100A7 have been proposed. 10,12,1415 Seminal studies reported that S100A7 has antibacterial activity against Escherichia coli , a microbe that rarely colonizes the skin and oral cavity.…”

mentioning

confidence: 99%

Biochemical and Functional Evaluation of the Intramolecular Disulfide Bonds in the Zinc-Chelating Antimicrobial Protein Human S100A7 (Psoriasin)

et al. 2017

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Human S100A7 (psoriasin) is a metal-chelating protein expressed by epithelial cells. It is a 22-kDa homodimer with two EF-hand domains per subunit, and two transition-metal-binding His3Asp sites at the dimer interface. Each subunit contains two cysteine residues that can exist as free thiols (S100A7red) or as an intramolecular disulfide bond (S100A7ox). Herein, we examine the disulfide bond redox behavior, the Zn(II) binding properties, and the antibacterial activity of S100A7, as well as the effect of Ca(II) ions on these properties. In agreement with prior work, (Hein et al. Proc. Natl. Acad. Sci. U. S. A. 2013, 112, 13039–13044), we show that apo S100A7ox is a substrate for the mammalian thioredoxin system; however, negligible reduction of the disulfide bond is observed for Ca(II)- and Zn(II)-bound S100A7ox. Furthermore, metal binding depresses the midpoint potential of the disulfide bond. S100A7ox and S100A7red each coordinate two equivalents of Zn(II) with sub-nanomolar affinity in the absence and presence of Ca(II) ions, and the cysteine thiolates in S100A7red do not form a third high-affinity Zn(II) site. These results refute a prior model implicating the Cys thiolates of S100A7red in high-affinity Zn(II) binding (Hein et al. Proc. Natl. Acad. Sci. U. S. A. 2013, 112, 13039–13044). S100A7ox and the disulfide-null variants show comparable Zn(II)-depletion profiles; however, only S100A7ox exhibits antibacterial activity against several bacterial species. Metal substitution experiments suggest that the disulfide bonds in S100A7 may enhance metal sequestration by the His3Asp sites and thereby confer growth inhibitory properties to S100A7ox.

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“…The calcium-binding proteins S100A7 (psoriasin), S100A8 (MRP8 or calgranulin A), S100A9 (MRP14 or calgranulin B), and the latters' heterodimeric form S100A8/A9 (calprotectin) were investigated in detail in patients with CRSsNP and CRSwNP for their antimicrobial effects and their possible implication in deficiencies in the barrier function of airway mucosal epithelium (Glaser et al, 2005;Meyer et al, 2008;Tieu et al, 2010). S100 proteins also show the typical parameters of DAMPs when released to the extracellular milieu, where they activate TLR4 (Vogl et al, 2007;Loser et al, 2010) and possibly RAGE (Sparvero et al, 2009).…”

Section: Damage Associated Molecular Patternsmentioning

confidence: 99%

“…The S100 proteins are products of a multigene family widely expressed in ECs; in addition to direct antimicrobial effects, these have diverse effects on cell differentiation and wound healing (Meyer et al, 2008). Palate lung nasal epithelial clone (PLUNC) is secreted by glandular rather than surface epithelium and this protein may have particular relevance for airway disease as it possesses antibiofilm properties.…”

mentioning

confidence: 99%