The human epidermal differentiation complex: cornified envelope precursors, S100 proteins and the ‘fused genes’ family

Abstract

The skin is essential for survival and protects our body against biological attacks, physical stress, chemical injury, water loss, ultraviolet radiation and immunological impairment. The epidermal barrier constitutes the primordial frontline of this defense established during terminal differentiation. During this complex process proliferating basal keratinocytes become suprabasally mitotically inactive and move through four epidermal layers (basal, spinous, granular and layer, stratum corneum) constantly adapting to the needs of the respective cell layer. As a result, squamous keratinocytes contain polymerized keratin intermediate filament bundles and a water-retaining matrix surrounded by the cross-linked cornified cell envelope (CE) with ceramide lipids attached on the outer surface. These cells are concomitantly insulated by intercellular lipid lamellae and hold together by corneodesmosmes. Many proteins essential for epidermal differentiation are encoded by genes clustered on chromosomal human region 1q21. These genes constitute the 'epidermal differentiation complex' (EDC), which is divided on the basis of common gene and protein structures, in three gene families: (i) CE precursors, (ii) S100A and (iii) S100 fused genes. EDC protein expression is regulated in a gene and tissue-specific manner by a pool of transcription factors. Among them, Klf4, Grhl3 and Arnt are essential, and their deletion in mice is lethal. The importance of the EDC is further reflected by human diseases: FLG mutations are the strongest risk factor for atopic dermatitis (AD) and for AD-associated asthma, and faulty CE formation caused by TG1 deficiency causes life-threatening lamellar ichthyosis. Here, we review the EDC genes and the progress in this field.

Filaggrin has evolved from an “S100 fused‐type protein” (SFTP) gene present in a common ancestor of amphibians and mammals

“…[4,5] The aggregation of keratin filaments, the control of denucleation of cornifying keratinocytes and the supply of amino acid components of the so-called natural moisturizing factor have been suggested as important functions of filaggrin and other SFTPs within keratinocyte-derived epithelia. [2,[6][7][8][9][10] …”

“…[1][2][3] SFTPs consist of an amino-terminal S100 domain and a long (up to more than 3000 amino acid residues) carboxyterminal domain that contains multiple sequence repeats. Mutations of the gene encoding filaggrin are associated with skin barrier defects in ichthyosis vulgaris and atopic dermatitis.…”

Role of genetic aspect in pathogenesis of atopic dermatitis

“…The cornified envelope consists of specialized proteins: loricrin (LOR), small proline-rich proteins (SPRR), a family of fused-type S100 proteins composed of filaggrin (FLG), repetin (RPTN), cornulin (CRNN), hornein (HRNR), and late cornified envelope-like proline-rich 1 (LELP1). Genes encoding these proteins are found within the epidermal differentiation complex (EDC), a gene cluster whose products are responsible for the final diversification of keratinocytes (Kypriotou et al 2012). These proteins form a thick layer resistant to physical and chemical factors, influence production of natural moisturizing compound and ensure the appropriate pH of the skin, that prevents the penetration of infectious factors to its deeper layers.…”

Epidermal differentiation complex (locus 1q21) gene expression in head and neck cancer and normal mucosa

“…They are expressed primarily in skin and are regulated by UV irradiation and calcium [9]. Their expression is altered in skin diseases -psoriasis and atopic dermatitis [1].…”

“…These genes are divided into three families encoding: cornified cell envelope (CE) precursors (involucrin, loricrin, small proline-rich proteins -SPRRs and the "late cornified envelope" proteins, LCEs), calcium-binding proteins (S100) with EF-hand domains, and "fused gene" proteins (SFTPs, 'S100 Fused Type proteins') involving filaggrin, filaggrin-2, repetin, trichohyalin, cornulin and hornerin [1]. Epidermal differentiation molecules are important especially for a plethora of skin diseases [1]. They may also constitute an important feature differentiating squamous cell carcinomas (SCC) from other types of cancer, e.g.…”