Novel S100A7 (psoriasin)/S100A15 (koebnerisin) subfamily: highly homologous but distinct in regulation and function

Abstract

S100A7 (psoriasin) and S100A15 (koebnerisin) were first identified in inflamed psoriatic skin. They are of major interest because of their putative functional roles in innate immunity, epidermal cell maturation, and epithelial tumorigenesis. Human S100A7 and S100A15 have lately evolved by gene duplications within the epidermal differentiation complex (chromosome 1q21) during primate evolution forming a novel S100 subfamily. Therefore, S100A7 and S100A15 are almost identical in sequence (>90%) and are difficult to discriminate. Despite their high homology, S100A7 and S100A15 are distinct in tissue distribution, regulation, and function, and thus, exemplary for the diversity within the S100 family. Their different properties are compelling reasons to discriminate S100A7 (psoriasin) and S100A15 (koebnerisin) in epithelial homeostasis, inflammation, and cancer.

Figure1:. Genomic structure of the human S100A7/S10015 subfamily.

Schematic representation of the genomic and exon/intron organization for the S100A7 and the S100A15 genes. Boxes represent exons, hatched regions indicate the coding sequence; intervening lines denote introns. The alternate S100A15 mRNA-splice variants are marked A for hS100A15-L (long) and B for hS100A15-S (short).

Figure2:. Protein structure of the human S100A7/S10015 subfamily.

Alignment of the predicted amino acid sequences of the human S100A7 (hS100A7, NP_002954) with the human S100A15 (hS100A15, NP_79669). Identical amino acid residues are indicated as blue boxes, and chemically similar amino acids are marked as grey boxes. Predicted EF-hand motifs for both proteins are marked above the sequences (variant S100-specific motif: amino acids 12–39, canonical EF-hand: amino acids 54–82).

Figure3:. hS100A7 and hS100A15 function through distinct classes of receptors.

A) Frozen sections of inflamed lesional psoriasis were stained for hS100A7 (green) and hS100A15 (red) showing differential upregulation of both S100 proteins. Nuclei were stained with DAPI (blue). Bar size: 50 μm. B) Recombinant hS100A7, hS100A15 were injected intraperitoneally into C57/BL6 wild-type mice alone or premixed in combination. After four hours, cells attracted into the peritoneal fluid were counted and analyzed by flow cytometry using the granulocyte marker Gr-1. (mean value + s.d. from six mice, * P ≤ 0.05). C) hS100A7 mediates leukocyte chemotaxis through RAGE (receptor of advanced glycated end products). This atypical chemotaxis receptor is pertussis toxin-insensitive, which helps distinguish ligand activity through classical chemokine receptors. hS100A15 chemotactic activity is Gi-protein-dependent, however the receptor has to be specified.

Figure 4:. S100A7 and S100A15 function through distinct classes of receptors.

a Frozen skin sections were stained for S100A7 (green) and S100A15 (red) showing their upregulation and differential distribution in normal skin compared to psoriasis. Nuclei were stained with DAPI (blue). Bar 50 μm. b S100A7 mediates leukocyte chemotaxis through RAGE (receptor of advanced glycated end products). This atypical chemotaxis receptor is pertussis toxin-insensitive, which helps to distinguish ligand activity through classical chemokine receptors. S100A15 chemotactic activity is Gi protein-dependent, but the receptor has yet to be specified. The distinct mechanisms of actions within the S100A7 (psoriasin)/S100A15 (koebnerisin) subfamily contribute to their synergistic effect in inflammation