Lce1 Family Members Are Nrf2-Target Genes that Are Induced to Compensate for the Loss of Loricrin

Abstract

Loricrin is a major component of the cornified cell envelope, a highly insoluble structure composed of covalently cross-linked proteins. Although loricrin knockout mice only exhibit a mild transient phenotype at birth, they show a marked delay in the formation of an epidermal barrier in utero. We recently discovered that induction of a compensatory response to repair the defective barrier is initiated by amniotic fluid via activation of NF-E2-related factor 2 and identified Sprr2d and Sprr2h as direct transcriptional targets. Proteomic analysis suggested that other proteins were also incorporated into the loricrin knockout cell envelope, in addition to the small proline rich proteins. Here we present evidence suggesting that the late cornified envelope 1 proteins are also compensatory components as determined by their localization within the loricrin knockout cell envelope via immunoelectron microscopy. We also demonstrate that late cornified envelope 1 genes are upregulated at the transcriptional level in loricrin knockout mouse skin and confirm that late cornified envelope 1 genes are transcriptional targets of NRF2. Our present study further highlights the complexity and importance of a compensatory mechanism that evolved in terrestrial animals to ensure the formation of a functional epidermal barrier.

Identification and comparative analysis of the epidermal differentiation complex in snakes

“…The new data therefore indicate that the process of keratinocyte cornification in the epidermis of snakes requires the participation of numerous proteins aside CBPs, like in other sauropsids. While crucial roles of mammalian EDC genes such as loricrin, LCEs, trichohyalin, and filaggrin in the skin barrier of mammals have been defined by a long series of studies4849505152, the identification of the EDC gene complement of snakes is the pivotal starting point for a comprehensive investigation of epidermal differentiation in this important subgroup of reptiles.…”

Abnormal keratinocyte differentiation in the nasal planum of Labrador Retrievers with hereditary nasal parakeratosis (HNPK)

“…Homozygous loricrin knockout mice are born with visible skin lesions such as erythroderma and shiny, translucent skin [33]. However, this phenotype normalizes 4-5 days after birth and is not associated with any histopathological abnormalities due to compensatory mechanisms [33,34]. The existence of a similar back-up system in the dog has not yet been investigated.…”

Loricrin Confers Photoprotective Function against UVB in Corneocytes

“…The physical properties of the stratum corneum (SC) are attributed to the formation of a specialized structure, the cornified cell envelope (CE). The CE reinforcement process incorporates loricrin (LOR), filaggrin (FLG), keratin intermediate filaments, and other space-filling small molecular proteins, such as small proline-rich proteins and the late cornified envelope proteins (Ishitsuka et al, 2016;Kalinin et al, 2002). This process is of particular importance in corneocyte maturation as it results in marked detergent insolubility and resilience through g-glutamyl lysine isopeptide bonds.…”