Photo Credit: Maryna Olyak

The following is a summary of “Prolyl Endopeptidase Is Involved in Filaggrinolysis and Cornification,” published in the January 2025 issue of Dermatology by Briot et al. 

FLG is a key biomarker for atopic dermatitis and skin dryness, with its proteolysis (filaggrinolysis) generating the natural moisturizing factor, though some involved proteases remain unidentified.  

Researchers conducted a retrospective study to identify candidate peptidases involved in the filaggrinolysis process.  

They analyzed 16 omics datasets and identified prolyl endopeptidase (PREP) as a potential peptidase involved in filaggrinolysis, PREP localization in the granular and deep cornified layers was determined through indirect immunofluorescence and confocal analysis, where it was colocalized with FLG. Tandem mass spectrometry and fluorescent quenching activity assays demonstrated PREP cleaving synthetic peptides derived from the FLG sequence, specifically at the carboxyl side of an internal proline. The PREP activity in the reconstructed human epidermis was inhibited using benzyloxycarbonyl-pro-prolinal and RNA interference was employed to reduce PREP expression in the reconstructed epidermis.  

The results showed that PREP cleaved FLG-derived synthetic peptides at the carboxyl side of an internal proline. Deimination of these peptides enhanced PREP enzymatic efficiency. Inhibiting PREP led to the accumulation of FLG monomers in the reconstructed human epidermis. Downregulation of PREP expression confirmed its role in FLG metabolism and keratinocyte differentiation. A significant reduction in bleomycin hydrolase and other cornification factors, such as loricrin, was observed which resulted in a drastic decrease in transepidermal electric resistance.  

Investigators concluded that PREP played a critical role in skin barrier function by regulating filaggrinolysis and keratinocyte differentiation, and its inhibition disrupts the processes, leading to altered cornification. 

Source: sciencedirect.com/science/article/abs/pii/S0022202X24004354