The roles of ABCA12 in keratinocyte differentiation and lipid barrier formation in the epidermis

Abstract

ABCA12 is a member of the large superfamily of ATP-binding cassette (ABC) transporters, which bind and hydrolyze ATP to transport various molecules across limiting membranes or into vesicles. The ABCA subfamily members are thought to be lipid transporters. ABCA12 is a keratinocyte transmembrane lipid transporter protein associated with the transport of lipids in lamellar granules to the apical surface of granular layer keratinocytes. Extracellular lipids, including ceramide, are thought to be essential for skin barrier function. ABCA12 mutations are known to underlie the three main types of autosomal recessive congenital ichthyoses: harlequin ichthyosis, lamellar ichthyosis and congenital ichthyosiform erythroderma. ABCA12 mutations lead to defective lipid transport via lamellar granules in the keratinocytes, resulting in malformation of the epidermal lipid barrier and ichthyosis phenotypes. Studies of ABCA12-deficient model mice indicate that lipid transport by ABCA12 is also indispensable for intact differentiation of keratinocytes.

Keywords: ABCA12; congenital ichthyosiform erythroderma; harlequin ichthyosis; lamellar granules; lamellar ichthyosis.

Figure 1

ABCA12 protein structure and domains. Analysis of the predicted structure of the ABCA12 protein reveals features typical of ABCA transporters.

Figure 2

Immunofluorescence labeling using ultrathin cryosections as substrates reveal that glucosylceramide (green) and ABCA12 (red) overlap in the granular layers (derived from ref. 5).

Figure 3

Scheme of ABCA12 distribution from the cis-Golgi, trans-Golgi network to lamellar granules in the upper spinous and granular layer keratinocytes (derived from ref. 5).

Figure 4

Physiological role(s) of ABCA12 in lipid trafficking of epidermal keratinocytes and the model of pathogenetic mechanisms in ichthyosis phenotypes caused by ABCA12 deficiency. (A) Model of how ABCA12 transports lipids in epidermal keratinocytes. (B) Model of how loss of ABCA12 function leads to lipid abnormality and lipid barrier malformation in the upper epidermis. (C) It is hypothesized that the combination of lipid barrier defects and disturbed keratinocyte differentiation cause hyperkeratosis and the ichthyosis phenotype (derived from ref. 20).