Keratins in Skin Epidermal Development and Diseases

Abstract

Epidermal keratinocyte (KC), the major cell type in the skin epidermis, plays critical roles in forming a permeability barrier to separate internal organs from external stimuli. Keratins, constituting about 30-80% of the total protein in KCs, form the major intermediate filament cytoskeleton of KC. Keratins consist of 54 unique genes in humans and they are expressed in cell-, differentiation-and development-dependent manner. While keratin pairs K5-K14 and K1-K10 are normally associated with KCs at different cell differentiation stages, other keratin pairs such as K6-K16/K17 and K8-K18 and are usually not expressed in normal skin interfollicular epidermis, but are elevated during wounding, inflammatory skin diseases such as psoriasis or malignant conversion of KC. The expression and function of keratins are tightly regulated at both transcriptional and post-transcriptional levels. Inherited or spontaneous mutations in keratins or abnormal keratin regulations or modifications can cause KC and cutaneous tissue fragility, skin hypertrophic and inflammatory conditions or malignant transformation of KC, therefore accounting for a large number of disorders in human skin. Here we review the recent literature on how keratins are normally expressed during skin development and how mutations or misregulations of these keratins are involved in the pathogenesis of skin diseases.

Keratin 6, 16 and 17—Critical Barrier Alarmin Molecules in Skin Wounds and Psoriasis

“…As the first physical and immunological barrier of the human body, the skin is a highly specialized organ composed of three primary layers: the outermost epidermis, the dermis and dermal white adipose tissue [1,2,3,4]. The epidermis, derived from a single layer of progenitor cells in embryos to a multilayered stratified epithelium during development, is at the front line of defense and is constantly exposed to a variety of environmental insults such as mechanical trauma, pathogens and chemical irritations [5,6,7]. As a result, keratinocytes, the most abundant cell type of the skin epidermis, has evolved to provide rapid and situation-specific innate immune responses upon sensing danger signals.…”

“…Keratins (KRT), the major components of the epithelial cytoskeleton, are responsible for maintaining the structural stability and integrity of keratinocytes. So far, more than 54 mammalian keratins have been identified, contributing to ~30–80% of total protein and forming the ~10 nm intermediate filaments (IFs) in keratinocytes [7,8,9]. These highly diverse keratins are subdivided into two classes based on their pH: The acidic type I keratins (KRT9-KRT40) and the neutral–basic type II keratins (KRT1-KRT8) [10,11,12].…”

“…For example, in the interfollicular epidermis, KRT14-KRT5 is the major type I-type II keratin pair expressed in proliferative basal keratinocytes, whereas differentiated keratinocytes in the suprabasal layers downregulate KRT14-KRT5 and express KRT10-KRT1 as the major keratin pair. During wounding, stressed keratinocytes rapidly induce de novo transcription of KRT16/17-KRT6, whose expression is normally restricted to epidermal cells of glabrous skin, the oral mucosa, and several appendages [7].…”

“…Keratin IFs extend from the desmosomes to the nuclear membrane, providing tissue resilience to resist environmental stresses [20]. In addition to providing structural support to epithelial cells, growing evidence has shown that keratins also regulate cell proliferation, migration, adhesion and inflammatory features of keratinocytes [7,16,21]. Mutation or abnormal expression of keratin proteins is associated with a variety of skin diseases, such as skin blistering diseases (Epidermolysis bullosa simplex and Epidermolytic hyperkeratosis), psoriasis and skin tumors (squamous cell carcinoma and basal cell carcinoma).…”

Expression profiling revealed keratins and interleukins as potential biomarkers in squamous cell carcinoma of horn in Indian bullocks (Bos indicus)

“…More than 50 mammalian keratins (type I and II) have been identified and characterized which usually coexpressed as a heterodimer between type I (acidic) and type II (basic). The prime role of the keratin intermediate filament cytoskeleton is to offer cells with structural flexibility (Zhang 2018). Thus, according to necessity, expression of type keratins defers according to cell types (normal or cancerous).…”