Affiliation:
1. Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) University of Toulouse, CNRS, INSERM, UPS Toulouse France
2. L'Oréal Research and Innovation, Aulnay‐sous‐bois Aulnay‐sous‐bois France
3. Centre de Microscopie Electronique Appliquée à la Biologie Université de Toulouse Toulouse France
Abstract
AbstractAbsence of a functional proteasome in the suprabasal layers of the epidermis is responsible for keratosis linearis with ichthyosis congenital and sclerosing keratoderma syndrome. Patient epidermis shows hypergranulosis associated with abnormally shaped keratohyalin granules and abnormal distribution of filaggrin in the Stratum granulosum and Stratum corneum. This suggests that the proteasome is involved in the degradation of filaggrin. To test this hypothesis, the proteasome proteolytic activity was inhibited in 3D reconstructed human epidermis (RHE) with the specific clasto‐lactacystin β‐lactone inhibitor. Confirming the efficacy of inhibition, ubiquitinated proteins accumulated in treated RHEs as compared to controls. Levels of urocanic acid (UCA) and pyrrolidone carboxylic acid (PCA), the end products of filaggrin degradation, were reduced. However, neither filaggrin accumulation nor appearance of filaggrin‐derived peptides were observed. On the contrary, the amount of filaggrin was shown to decrease, and a similar tendency was observed for profilaggrin, its precursor. Accumulation of small cytoplasmic vesicles associated with a significant increase in autophagy markers indicated activation of the autophagy process upon proteasome inhibition. Taken together, these results suggest that the perturbation of UCA and PCA production after proteasome inhibition was probably due to down‐regulation of filaggrin expression rather than to blocking of filaggrin proteolysis.
Subject
Dermatology,Molecular Biology,Biochemistry
Cited by
2 articles.
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