Loricrin: Past, Present, and Future

Abstract

The terminal differentiation of the epidermis is a complex physiological process. During the past few decades, medical genetics has shown that defects in the stratum corneum (SC) permeability barrier cause a myriad of pathological conditions, ranging from common dry skin to lethal ichthyoses. Contrarily, molecular phylogenetics has revealed that amniotes have acquired a specialized form of cytoprotection cornification that provides mechanical resilience to the SC. This superior biochemical property, along with desiccation tolerance, is attributable to the proper formation of the macromolecular protein-lipid complex termed cornified cell envelopes (CE). Cornification largely depends on the peculiar biochemical and biophysical properties of loricrin, which is a major CE component. Despite its quantitative significance, loricrin knockout (LKO) mice have revealed it to be dispensable for the SC permeability barrier. Nevertheless, LKO mice have brought us valuable lessons. It is also becoming evident that absent loricrin affects skin homeostasis more profoundly in many more aspects than previously expected. Through an extensive review of aggregate evidence, we discuss herein the functional significance of the thiol-rich protein loricrin from a biochemical, genetic, pathological, metabolic, or immunological aspect with some theoretical and speculative perspectives.

Regulation of Filaggrin, Loricrin, and Involucrin by IL-4, IL-13, IL-17A, IL-22, AHR, and NRF2: Pathogenic Implications in Atopic Dermatitis

“…LOR is the most abundant component of the cornified envelope [1,3,5]. It is very hydrophobic, insoluble, and is easily polymerized via disulfide crosslinking in ambient air, making it suitable as a protein that reinforces the cornified envelope [1,5]. LOR is expressed in the granular layer and is crosslinked to IVL, envoplakin, and periplakin scaffolds by transglutaminase 1 [1,5].…”

“…Profilaggrin to FLG processing requires several proteases, such as profilaggrin endopeptidase 1, matriptase 1, and channel-activating protease 1. FLG is involved in aggregating the K1 and K10 filaments into higher-molecular-weight parallel structures that facilitate the incorporation of K1 and K10 into the cornified envelope and contribute to the thin granular keratinocyte shape [1,5,53]. FLG peptides are simultaneously degraded by caspase 14 and calpain 1 into free hydrophilic amino acids, which maintain the intracellular water content [1,5,6].…”

“…The human epidermis is composed of stratified layers, differentiating from the basal layer on the basement membrane, towards spinous and granular layers, and finally to the outermost cornified layer [1][2][3][4][5][6]. Keratinocytes are the major constituent of epidermal cells.…”

“…Keratins connect to the desmosomes, which are the cell-cell adhesion structures specific for stratified epithelium [1][2][3][4][5][6]. In the granular layer, keratinocytes commit to synthesize keratohyalin granules, which are primarily composed of profilaggrin and loricrin (LOR) [1][2][3][4][5][6]. This process coincides with the decreases of K1 and K10, increase of calcium and activation of protein kinase C [2].…”

“…The cornified cells provide a specialized cell membrane called the cornified envelope. The cornified envelope is composed of various cytoskeletal and barrier-related molecules, including K1, K10, desmosomal proteins (envoplakin and periplakin), LOR, FLG, filaggrin-2 (FLG2), and involucrin (IVL), which are crosslinked by transglutaminase 1 and partly by transglutaminases 3 and 5 [1][2][3][4][5][6]. Granular layer keratinocytes also produce lamellar granules, which are rich in polar lipids, glycosphingolipids, free sterols, and phospholipids.…”