The KEAP1/NRF2 Signaling Pathway in Keratinization

• Published in: Antioxidants Vol. 9; no. 8; p. 751
• Main Authors: Ishitsuka, Yosuke, Ogawa, Tatsuya, Roop, Dennis
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 14.08.2020; MDPI
• Subjects: Acne; Adaptation; Animal models; Assaults; Atopic dermatitis; Body wall; environmental response; Evolution; Gene expression; gene expression regulation; Genotype & phenotype; Health aspects; Homeostasis; KEAP1/NRF2 signaling; Keratin; Keratinization; Keratinocytes; Metabolism; Permeability; Phenotypes; Proteins; Psoriasis; Reptiles & amphibians; Review; Signal transduction; Skin; Skin diseases; squamous epithelium; Structure-function relationships; Sulfur; thiol; Japan; environmental response; gene expression regulation; thiol; disulfide; keratinization; KEAP1/NRF2 signaling; squamous epithelium; loricrin
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox9080751

Keratinization is a tissue adaptation, but aberrant keratinization is associated with skin disorders such as ichthyoses, atopic dermatitis, psoriasis, and acne. The disease phenotype stems from the interaction between genes and the environment; therefore, an understanding of the adaptation machinery may lead to a new appreciation of pathomechanisms. The KEAP1/NRF2 signaling pathway mediates the environmental responses of squamous epithelial tissue. The unpredicted outcome of the -null mutation in mice allowed us to revisit the basic principle of the biological process of keratinization: sulfur metabolism establishes unparalleled cytoprotection in the body wall of terrestrial mammals. We summarize the recent understanding of the KEAP1/NRF2 signaling pathway, which is a thiol-based sensor-effector apparatus, with particular focuses on epidermal differentiation in the context of the gene-environment interaction, the structure/function principles involved in KEAP1/NRF2 signaling, lessons from mouse models, and their pathological implications. This synthesis may provide insights into keratinization, which provides physical insulation and constitutes an essential innate integumentary defense system.