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Filaggrin and filaggrin 2 processing are linked together through skin aspartic acid protease activation.

ABSTRACT: Skin aspartic acid protease (SASPase) is believed to be a key enzyme involved in filaggrin processing during epidermal terminal differentiation. Since little is known about the regulation of SASPase function, the aim of this study was to identify involved protein partners in the process. Yeast two hybrid analyses using SASPase as bait against a human reconstructed skin library identified that the N-terminal domain of filaggrin 2 binds to the N-terminal fragment of SASPase. This interaction was confirmed in reciprocal yeast two hybrid screens and by Surface Plasmon Resonance analyses. Immunohistochemical studies in human skin, using specific antibodies to SASPase and the N-terminal domain of filaggrin 2, showed that the two proteins partially co-localized to the stratum granulosum. In vitro enzymatic assays showed that the N-terminal domain of filaggrin 2 enhanced the autoactivation of SASPase to its 14 kDa active form. Taken together, the data suggest that the N-terminal domain of filaggrin 2 regulates the activation of SASPase that may be a key event upstream of filaggrin processing to natural moisturizing factors in the human epidermis.

SUBMITTER: Donovan M

PROVIDER: S-EPMC7241785 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Filaggrin and filaggrin 2 processing are linked together through skin aspartic acid protease activation.

Donovan Mark M Salamito Mélanie M Thomas-Collignon Agnès A Simonetti Lucie L Desbouis Stephanie S Rain Jean-Christophe JC Formstecher Etienne E Bernard Dominique D

PloS one 20200521 5

Skin aspartic acid protease (SASPase) is believed to be a key enzyme involved in filaggrin processing during epidermal terminal differentiation. Since little is known about the regulation of SASPase function, the aim of this study was to identify involved protein partners in the process. Yeast two hybrid analyses using SASPase as bait against a human reconstructed skin library identified that the N-terminal domain of filaggrin 2 binds to the N-terminal fragment of SASPase. This interaction was c ...[more]

PMID: 32437351

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Project description:BackgroundThe filaggrin protein is important for skin barrier structure and function. Loss-of-function (null) mutations in the filaggrin gene FLG may increase dermal absorption of chemicals.ObjectiveThe objective of the study was to clarify if dermal absorption of chemicals differs depending on FLG genotype.MethodWe performed a quantitative real-time polymerase chain reaction (qPCR)-based genetic screen for loss-of-function mutations (FLG null) in 432 volunteers from the general population in southern Sweden and identified 28 FLG null carriers. In a dermal exposure experiment, we exposed 23 FLG null and 31 wild-type (wt) carriers to three organic compounds common in the environment: the polycyclic aromatic hydrocarbon pyrene, the pesticide pyrimethanil, and the ultraviolet-light absorber oxybenzone. We then used liquid-chromatography mass-spectrometry to measure the concentrations of these chemicals or their metabolites in the subjects' urine over 48 h following exposure. Furthermore, we used long-range PCR to measure FLG repeat copy number variants (CNV), and we performed population toxicokinetic analysis.ResultsLag times for the uptake and dermal absorption rate of the chemicals differed significantly between FLG null and wt carriers with low (20-22 repeats) and high FLG CNV (23-24 repeats). We found a dose-dependent effect on chemical absorption with increasing lag times by increasing CNV for both pyrimethanil and pyrene, and decreasing area under the urinary excretion rate curve (AUC(0-40h)) with increasing CNV for pyrimethanil. FLG null carriers excreted 18% and 110% more metabolite (estimated by AUC(0-40h)) for pyrimethanil than wt carriers with low and high CNV, respectively.ConclusionWe conclude that FLG genotype influences the dermal absorption of some common chemicals. Overall, FLG null carriers were the most susceptible, with the shortest lag time and highest rate constants for skin absorption, and higher fractions of the applied dose excreted. Furthermore, our results indicate that low FLG CNV resulted in increased dermal absorption of chemicals. https://doi.org/10.1289/EHP7310.

Dataset Information

Filaggrin and filaggrin 2 processing are linked together through skin aspartic acid protease activation.

Publications

Filaggrin and filaggrin 2 processing are linked together through skin aspartic acid protease activation.

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