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Related Concept Videos

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Filopodia are thin, actin-rich cellular protrusions that play an important role in many fundamental cellular functions. They vary in their occurrence, length, and positioning in different cell types, suggesting their diverse roles.
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Actin filaments (F-actin) are composed of actin subunits. The dissociation of actin monomers can occur from either end of F-actin. The rate of dissociation is faster from the minus-end or the pointed end, where the actin subunits exist with a bound ADP, together known as ADP-actin. The depolymerization of F-actin is aided by proteins, including the actin-depolymerizing factor (ADF) and cofilin family of proteins, gelsolin, and glia maturation factor (GMF).
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Disassembly of Intermediate Filaments01:35

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Intermediate filaments (IFs) do not undergo spontaneous disassembly. Enzymes, kinases, and phosphatases add and remove phosphates from specific sites to regulate their disassembly. The IF concentration in the cytoplasm also regulates the disassembly. If the concentration crosses a threshold, it activates the protein kinases in the vicinity, allowing the phosphorylation of IFs.
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Protein Folding Quality Check in the RER01:29

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ER is the primary site for the maturation and folding of soluble and transmembrane secretory proteins. The calnexin cycle is a specific chaperone system that folds and assesses the confirmation of N-glycosylated proteins before they can exit the ER lumen. The primary players of this quality check pipeline are the lectins, ER-resident chaperones, and a glucosyl transferase enzyme. In case the calnexin system in the lumen fails to salvage a misfolded protein, it is transported to the cytoplasm...
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Mechanism of Lamellipodia Formation01:31

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Cells migrating in response to external stimuli form lamellipodia, which are thin membrane protrusions supported by a mesh of linked, branched, or unbranched actin filaments. These actin filaments interact with myosin motor proteins, creating the dynamic actomyosin complex within the cytoskeleton. Contractility, or the ability to generate contractile stress, is inherent to the actomyosin complex. It helps cells detect the stiffness of the surrounding ECM and exert contractile force for...
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Export of Misfolded Proteins out of the ER01:32

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After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
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Updated: Jun 23, 2025

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Prolyl Endopeptidase Is Involved in Filaggrinolysis and Cornification.

Julie Briot1, Carole Pons1, Aude Foucher2

  • 1Toulouse Institute for Infectious and Inflammatory Diseases (INFINITy), University of Toulouse, INSERM UMR1291 - CNRS UMR5051, Toulouse, France.

The Journal of Investigative Dermatology
|June 15, 2024
PubMed
Summary

Prolyl endopeptidase (PREP) is identified as a key enzyme in filaggrinolysis, crucial for skin barrier function. Inhibiting PREP disrupts filaggrin processing and keratinocyte differentiation, impacting skin hydration and integrity.

Keywords:
EpidermisKeratinocytePost-translational modificationProteaseTerminal differentiation

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Area of Science:

  • Biochemistry
  • Dermatology
  • Molecular Biology

Background:

  • Filaggrin (FLG) proteolysis, or filaggrinolysis, generates natural moisturizing factors essential for skin hydration.
  • The complete enzymatic pathway of filaggrinolysis involves several proteases/peptidases, some of which remain unidentified.
  • FLG is a critical biomarker for atopic dermatitis and skin dryness.

Purpose of the Study:

  • To identify novel peptidase candidates involved in filaggrinolysis.
  • To investigate the role of prolyl endopeptidase (PREP) in FLG metabolism and keratinocyte differentiation.

Main Methods:

  • Bioinformatic analysis of 16 omics datasets to identify candidate peptidases.
  • Immunofluorescence and confocal microscopy to determine PREP localization relative to FLG.
  • Tandem mass spectrometry and activity assays to assess PREP's enzymatic activity on FLG-derived peptides.
  • Inhibition and RNA interference studies in reconstructed human epidermis to evaluate PREP's functional impact.
  • Quantitative proteomics, western blotting, and RT-qPCR to analyze protein and gene expression changes.
  • Measurement of transepidermal electrical resistance (TEER) to assess skin barrier function.

Main Results:

  • PREP was identified as a candidate peptidase and localized to granular and deep cornified layers, colocalizing with FLG.
  • PREP demonstrated enzymatic activity, cleaving FLG-derived peptides at the carboxyl side of proline residues, with enhanced efficiency upon deimination.
  • Specific inhibition or downregulation of PREP led to FLG monomer accumulation and reduced expression of other cornification markers, including bleomycin hydrolase and loricrin.
  • Functional assays showed a significant reduction in transepidermal electric resistance upon PREP modulation, indicating impaired skin barrier function.

Conclusions:

  • PREP plays a significant role in filaggrinolysis and keratinocyte differentiation.
  • PREP's activity is crucial for proper FLG processing and the maintenance of skin barrier integrity.
  • Targeting PREP could offer a novel therapeutic strategy for conditions associated with impaired skin barrier function, such as atopic dermatitis.