CGI-58 Is an α/β-Hydrolase within Lipid Transporting Lamellar Granules of Differentiated Keratinocytes

Abstract

CGI-58 is the causative molecule underlying DorfmanChanarin syndrome, a neutral lipid storage disease exhibiting apparent clinical features of ichthyosis. CGI-58, associated with triacylglycerol hydrolysis, has an ␣/␤-hydrolase fold and is also known as the ␣/␤-hydrolase domain-containing protein 5. The purpose of this study was to elucidate the function of CGI-58 and the pathogenic mechanisms of ichthyosis in Dorfman-Chanarin syndrome. Using an anti-CGI-58 antibody, we found CGI-58 to be expressed in the upper epidermis, predominantly in the granular layer cells, as well as in neurons and hepatocytes. Immunoelectron microscopy revealed that CGI-58 was also localized to the lamellar granules (LGs), which are lipid transport and secretion granules found in keratinocytes. CGI-58 expression was markedly reduced in the epidermis of patients with harlequin ichthyosis, demonstrating defective LG formation. In cultured keratinocytes, CGI-58 expression was mildly up-regulated under high Ca 2؉ conditions and markedly up-regulated in three-dimensional, organotypic cultures. In the developing human epidermis, CGI-58 immunostaining was observed at an estimated gestational age of 49 days, and CGI-58 mRNA expression was up-regulated concomitantly with both epidermal stratification and keratinocyte differentiation. CGI-58 knockdown reduced expression of keratinocyte differentiation/keratinization markers in cultured human keratinocytes. Our results indicate that CGI-58 is expressed and packaged into LGs during keratinization and likely plays crucial role(s) in keratinocyte differentiation and LG lipid metabolism, contributing to skin lipid barrier formation. (Am J Pathol

Epidermal triglyceride levels are correlated with severity of ichthyosis in Dorfman–Chanarin syndrome

“…It is, however, unclear why permeability barrier remained intact in our patient, while the water holding capacity was markedly decreased in the involved lesions. Akiyama and coworkers recently demonstrated that CGI-58 knockdown reduced expression of keratinocyte differentiation markers including filaggrin [13], which plays an important role in retaining stratum corneum water.…”

“…Previous studies demonstrated that the ultrastructure of DCS included abnormal lipid micro-inclusions within lamellar bodies and resulting lamellar/non-lamellar phase separation or clefts in the intercellular spaces of cornified layer [3,14,15]. Very recent study revealed that CGI-58 expression was increased during differentiation and localized in lamellar granules of keratinocytes and likely to be involved in barrier formation [13]. Given that TG is the content of lipid deposition in DCS, unsolved question is that the ultrastructural aberrancy in the epidermis is similar to other inherited, lipid storage diseases associated with ichthyosis, such as Refsum disease, Sjö gren-Larsson syndrome [15].…”

“…skin [9,13]. In patients with DCS, CGI-58 mutations were associated with defective formation of lamellar granules [14].…”

The N-terminal Region of Comparative Gene Identification-58 (CGI-58) Is Important for Lipid Droplet Binding and Activation of Adipose Triglyceride Lipase

“…8) are not competent for ATGL activation (1). CGI-58 mRNA is abundant in various tissues, including adipose tissue, liver, testis, neurons, muscle, and epidermis (1,9). Interestingly, mRNA expression levels of CGI-58 and ATGL do not correlate in the tissues tested (1, 10 -12).…”

Crucial Role of CGI-58/.ALPHA./.BETA. Hydrolase Domain-Containing Protein 5 in Lipid Metabolism

“…Furthermore, CGI-58 knockdown reduces the expression of keratinocyte differentiation markers in cultured human keratinocytes. 32) Thus, CGI-58 plays crucial roles in epidermal keratinocyte differentiation and LG lipid metabolism, thereby contributing to the formation of the skin's lipid barrier.…”