title: Cell death by cornification.
abstract: Epidermal keratinocytes undergo a unique form of terminal differentiation and programmed cell death known as cornification. Cornification leads to the formation of the outermost skin barrier, i.e. the cornified layer, as well as to the formation of hair and nails. Different genes are expressed in coordinated waves to provide the structural and regulatory components of cornification. Differentiation-associated keratin intermediate filaments form a complex scaffold accumulating in the cytoplasm and, upon removal of cell organelles, fill the entire cell interior mainly to provide mechanical strength. In addition, a defined set of proteins is cross-linked by transglutamination in the cell periphery to form the so-called cornified envelope. Extracellular modifications include degradation of the tight linkages between corneocytes by excreted proteases, which allows corneocyte shedding by desquamation, and stacking and modification of the excreted lipids that fill the intercellular spaces between corneocytes to provide a water-repellant barrier. In hard skin appendages such as hair and nails these tight intercorneocyte connections remain permanent. Various lines of evidence exist for a role of organelle disintegration, proteases, nucleases, and transglutaminases contributing to the actual cell death event. However, many mechanistic aspects of kearatinocyte death during cornification remain elusive. Importantly, it has recently become clear that keratinocytes activate anti-apoptotic and anti-necroptotic pathways to prevent premature cell death during terminal differentiation. This review gives an overview of the current concept of cornification as a mode of programmed cell death and the anti-cell death mechanisms in the epidermis that secure epidermal homeostasis. This article is part of a Special Section entitled: Cell Death Pathways.
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria. Electronic address: leopold.eckhart@meduniwien.ac.at.
authors.forename: Leopold
authors.initials: L
authors.lastname: Eckhart
authors.affiliation: Molecular Signaling and Cell Death Unit, Department for Molecular Biomedical Research, VIB, Ghent, Belgium; Molecular Cell Biology of the Skin Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Saskia
authors.initials: S
authors.lastname: Lippens
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Erwin
authors.initials: E
authors.lastname: Tschachler
authors.affiliation: Molecular Signaling and Cell Death Unit, Department for Molecular Biomedical Research, VIB, Ghent, Belgium; Molecular Cell Biology of the Skin Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium. Electronic address: wim.declercq@dmbr.vib-UGent.be.
authors.forename: Wim
authors.initials: W
authors.lastname: Declercq
mesh_terms: D000818:Animals; D016923:Cell Death; D002454:Cell Differentiation; D000078404:Epidermal Cells; D000091344:Filaggrin Proteins; D006801:Humans; D015603:Keratinocytes / Q000166:cytology*; D008954:Models, Biological
keywords: Apoptosis; Cornification; FLG; IKK; IκB kinase; K; KLK; Keratinocyte; NF-κB; NMFs; Necrosis; RIPK; SC; SG; TAK1; TGFβ-activated kinase; TGase; TNF; TUNEL; UCA; filaggrin; kallikrein; keratin; natural moisturizing factors; receptor interacting protein kinase; stratum corneum; stratum granulosum; terminal deoxynucleotidyl transferase dUTP nick end labeling; transglutaminase; tumor necrosis factor; urocanic acid