From Mice to Men: An Evolutionary Conserved Breakdown of the Epidermal Calcium Gradient and Its Impact on the Cornified Envelope

Cornified cells of the stratum corneum have a monolayer of an unusual lipid covalently attached to the outer surface. This is referred to as the corneocyte lipid envelope (CLE). It consists of a monolayer of ω-hydroxyceramides covalently attached to the outer surface of the cornified envelope. The CLE is essential for proper barrier function of the skin and is derived from linoleate-rich acylglucosylceramides synthesized in the viable epidermis. Biosynthesis of acylglucosylceramide and its conversion to the cornified envelope is complex. Acylglucosylceramide in the bounding membrane of the lamellar granule is the precursor of the CLE. The acylglucosylceramide in the limiting membrane of the lamellar granule may be oriented with the glucosyl moiety on the inside. Conversion of the acylglucosylceramide to the CLE requires removal of the glucose by action of a glucocerebrosidase. The ester-linked fatty acid may be removed by an as yet unidentified esterase, and the resulting ω-hydroxyceramide may become ester linked to the outer surface of the cornified envelope through action of transglutaminase 1. Prior to removal of ester-linked fatty acids, linoleate is oxidized to an epoxy alcohol through action of 2 lipoxygenases. This can be further oxidized to an epoxy-enone, which can spontaneously attach to the cornified envelope through Schiff’s base formation. Mutations of genes coding for enzymes involved in biosynthesis of the CLE result in ichthyosis, often accompanied by neurologic dysfunction. The CLE is recognized as essential for barrier function of skin, but many questions about details of this essentiality remain. What are the relative roles of the 2 mechanisms of lipid attachment? What is the orientation of acylglucosylceramide in the bounding membrane of lamellar granules? Some evidence supports a role for CLE as a scaffold upon which intercellular lamellae unfold, but other evidence does not support this role. There is also controversial evidence for a role in stratum corneum cohesion. Evidence is presented to suggest that covalently bound ω-hydroxyceramides serve as a reservoir for free sphingosine that can serve in communicating with the viable epidermis and act as a potent broad-acting antimicrobial at the skin surface. Many questions remain.

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Suprabasin—A Review

Genes ◽

10.3390/genes12010108 ◽

2021 ◽

Vol 12 (1) ◽

pp. 108

Author(s):

Miroslav Pribyl ◽

Zdenek Hodny ◽

Iva Kubikova

Keyword(s):

Glioblastoma Multiforme ◽

Poor Prognosis ◽

Current Knowledge ◽

Original Description ◽

Oesophageal Carcinoma ◽

Secreted Proteins ◽

Cornified Envelope ◽

Physiological Conditions ◽

Signalling Molecules ◽

Human Genes

Among the ~22,000 human genes, very few remain that have unknown functions. One such example is suprabasin (SBSN). Originally described as a component of the cornified envelope, the function of stratified epithelia-expressed SBSN is unknown. Both the lack of knowledge about the gene role under physiological conditions and the emerging link of SBSN to various human diseases, including cancer, attract research interest. The association of SBSN expression with poor prognosis of patients suffering from oesophageal carcinoma, glioblastoma multiforme, and myelodysplastic syndromes suggests that SBSN may play a role in human tumourigenesis. Three SBSN isoforms code for the secreted proteins with putative function as signalling molecules, yet with poorly described effects. In this first review about SBSN, we summarised the current knowledge accumulated since its original description, and we discuss the potential mechanisms and roles of SBSN in both physiology and pathology.

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