Epidermal differentiation: The role of proteases and their inhibitors

Zeeuwen, Patrick L.J.M.

doi:10.1078/0171-9335-00388

Cited by 119Skin and Cellular Biology ResearchProtease and Inhibitor MechanismsGenetic and rare skin diseases.

Epidermal differentiation: The role of proteases and their inhibitors

Zeeuwen, Patrick L.J.M.·2004·European Journal of Cell Biology

DOI 10.1078/0171-9335-00388

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Abstract

Dermatological diseases range from minor cosmetic problems to life-threatening conditions, as seen in some severe disorders of keratinization and cornification. These disorders are commonly due to abnormal epidermal differentiation processes, which result in disturbed barrier function of human skin. Elucidation of the cellular differentiation programs that regulate the formation and homeostasis of the epidermis is therefore of great importance for the understanding and therapy of these disorders. Much of the barrier function of human epidermis against the environment is provided by the cornified cell envelope (CE), which is assembled by transglutaminase (TGase)-mediated cross-linking of several structural proteins and lipids during the terminal stages of normal keratinocyte differentiation. The major constituents of the stratum corneum and the current knowledge on the formation of the stratum corneum will be briefly reviewed here. The discovery of mutations that underlie several human diseases caused by genetic defects in the protein or lipid components of the CE, and recent analyses of mouse mutants with defects in the structural components of the CE, catalyzing enzymes, and lipid processing, have highlighted their essential function in establishing the epidermal barrier. In addition, recent findings have provided evidence that a disturbed protease-antiprotease balance could cause faulty differentiation processes in the epidermis and hair follicle. The importance of regulated proteolysis in epithelia is well demonstrated by the recent identification of the SPINK5 serine proteinase inhibitor as the defective gene in Netherton syndrome, cathepsin C mutations in Papillon-Lefevre syndrome, cathepsin L deficiency infurless mice, targeted ablation of the serine protease Matriptase/MTSP1, targeted ablation of the aspartate protease cathepsin D, and the phenotype of targeted epidermal overexpression of stratum corneum chymotryptic enzyme in mice. Notably, our recent findings on the role of cystatin M/E and legumain as a functional dyad in skin and hair follicle cornification, a paradigm example of the regulatory functions exerted by epidermal proteases, will be discussed.

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Cornification critically relies on CASP14 and multiple transglutaminase isoforms and has long been considered a form of PCD.
“The latter process, which is commonly known as cornification (or keratinization) and critically relies on CASP14 [1026, 1027] and multiple isoforms of transglutaminase [1025, 1028, 1029], has long been considered as a form of PCD [1025, 1030].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [1028]

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Authors: Zeeuwen, P. L. J. M.
Affiliations: Radboud University Nijmegen (NL)
Corresponding author: Zeeuwen, Patrick L.J.M.
ORCID: Zeeuwen, Patrick L.J.M.
Venue: European Journal of Cell Biology
Publisher: Elsevier BV
Published: 2004
Volume: 83
Issue: 11-12
Pages: 761-773
ISSN: 0171-9335 (ISSN-L)
DOI: 10.1078/0171-9335-00388
OpenAlex: W2123850865
Cited by: 119
References: 193
Citations by year: 2026: 1 · 2025: 2 · 2024: 3 · 2023: 5 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 6 · 2017: 6 · 2016: 2 · 2015: 4 · 2014: 5 · 2013: 7 · 2012: 5
FWCI: 2.80
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
Locations: European Journal of Cell Biology (publishedVersion)
PubMed (publishedVersion)
Radboud Repository (Radboud University) (submittedVersion)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Skin and Cellular Biology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
Keywords: epidermal differentiation, keratinization, cornified envelope, skin barrier function, protease-antiprotease balance, stratum corneum formation, transglutaminase, keratinocyte differentiation, Netherton syndrome, SPINK5, cathepsin C, Papillon-Lefèvre syndrome, cathepsin L, matriptase, cathepsin D, legumain, keratinization disorders
MeSH terms: Epidermal Cells, Asparaginyl Endopeptidase, Animals, Cell Differentiation, Cysteine Endopeptidases, Epidermis, Humans, Peptide Hydrolases, Protease Inhibitors, Transglutaminases, Skin Diseases, Cystatins, Mice

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Epidermal differentiation: The role of proteases and their inhibitors

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