Abstract
Mal de Meleda is an autosomal recessive inflammatory and keratotic palmoplantar skin disorder due to mutations in the ARS B gene, encoding for SLURP-1 (secreted mammalian Ly-6/uPAR-related protein 1). SLURP-1 belongs to the Ly-6/uPAR superfamily of receptor and secreted proteins, which participate in signal transduction, immune cell activation or cellular adhesion. The high degree of structural similarity between SLURP-1 and the three fingers motif of snake neurotoxins and Lynx1 suggests that this protein interacts with the neuronal acetylcholine receptors. We found that SLURP-1 potentiates the human alpha 7 nicotinic acetylcholine receptors that are present in keratinocytes. These results identify SLURP-1 as a secreted epidermal neuromodulator which is likely to be essential for both epidermal homeostasis and inhibition of TNF-alpha release by macrophages during wound healing. This explains both the hyperproliferative as well as the inflammatory clinical phenotype of Mal de Meleda.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholine / metabolism
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Amino Acid Sequence
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Animals
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Antigens, Ly / chemistry
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Antigens, Ly / genetics*
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Antigens, Ly / isolation & purification
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Antigens, Ly / pharmacology
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Cell Line
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Cell Nucleus / metabolism
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Clone Cells
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DNA, Complementary / administration & dosage
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DNA, Complementary / metabolism
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Dose-Response Relationship, Drug
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Epidermis / metabolism*
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Female
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Genes, Recessive
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Humans
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Keratoderma, Palmoplantar / genetics*
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Keratoderma, Palmoplantar / metabolism
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Keratoderma, Palmoplantar / pathology
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Microinjections
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Models, Molecular
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Moths / cytology
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Mutation
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Neurotransmitter Agents / metabolism*
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Oocytes / metabolism
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Patch-Clamp Techniques
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Peptides / chemistry
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Peptides / genetics
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Peptides / metabolism
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Phenotype
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Protein Structure, Tertiary
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Receptors, Cholinergic / drug effects
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Receptors, Cholinergic / metabolism
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Recombinant Proteins / isolation & purification
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Recombinant Proteins / metabolism
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Urokinase-Type Plasminogen Activator / chemistry
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Urokinase-Type Plasminogen Activator / genetics*
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Urokinase-Type Plasminogen Activator / isolation & purification
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Urokinase-Type Plasminogen Activator / pharmacology
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Xenopus laevis / physiology
Substances
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Antigens, Ly
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DNA, Complementary
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Neurotransmitter Agents
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Peptides
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Receptors, Cholinergic
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Recombinant Proteins
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SLURP1 protein, human
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Urokinase-Type Plasminogen Activator
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Acetylcholine