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.

AKT1-mediated Lamin A/C degradation is required for nuclear degradation and normal epidermal terminal differentiation

“…Nuclear degradation is a key stage in keratinocyte terminal differentiation and the formation of the cornified envelope that comprises the majority of epidermal barrier function. [1][2][3] Parakeratosis, the retention of nuclear material in the cornified layer of the epidermis, is a common histological observation in many skin diseases, but most notably in the epidermal barrierdefective diseases eczema and psoriasis. 4,5 Mechanisms of nuclear degradation in the epidermis have not yet been well characterised and it is not known whether the retained nuclei contribute to the altered epidermal differentiation programmes seen in these skin diseases.…”

The Reduction-insensitive Bonds of the MUC2 Mucin Are Isopeptide Bonds

“…analogy to human skin where transamidation is important for stabilizing the multilayered cornified outer skin surface built by dead cells (29). This is very important for protecting us from outer environmental damage.…”

Lysosomes in programmed cell death pathways: from initiators to amplifiers

“…Corneocytes -dead keratinocytes -become part of the outer skin barrier, fundamental for protection against mechanical, chemical or biological stressors. During this 2-weeks' long cellular transformation, various enzymes become involved in organelle degradation, such as proteases, nucleases, and transglutaminases (Lippens et al, 2009;Eckhart et al, 2013). After degradation, free areas within the cell are replaced by cytoskeleton and a cornified cell envelope is created at the intracellular edges of the cell.…”

“…Moreover, the transglutaminase activity is also dependent on release of cathepsins from lysosomes and Ca 2+ from endoplasmic reticulum and thereby on cystatin E/M cathepsin L/V axis. However, calpain-1-dependent LMP, which is triggered after tight envelope formation to prevent uncontrolled degradation, occurs from unknown reason Eckhart et al, 2013;Costanzo et al, 2015). Anyhow, dysregulation of proteases and their inhibitors in the skin might be related to development of various diseases, such as Netherton syndrome, Papillon-Lefevre syndrome as well as impaired skin barrier function (Zeeuwen, 2004;Cheng et al, 2009;Zeeuwen et al, 2009;Jansen et al, 2012).…”