CGI-58 is an alpha/beta-hydrolase within lipid transporting lamellar granules of differentiated keratinocytes.
CGI-58 is the causative molecule underlying Dorfman-Chanarin syndrome, a neutral lipid storage disease exhibiting apparent clinical features of ichthyosis. CGI-58, associated with triacylglycerol hydrolysis, has an alpha/beta-hydrolase fold and is also known as the alpha/beta-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.
Akiyama
Masashi
M
Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo 060-8638, Japan. akiyama@med.hokudai.ac.jp
Sakai
Kaori
K
Takayama
Chitoshi
C
Yanagi
Teruki
T
Yamanaka
Yasuko
Y
McMillan
James R
JR
Shimizu
Hiroshi
H
D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001692:Biological Transport; D001921:Brain / Q000166:cytology / Q000201:enzymology; D002454:Cell Differentiation; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000201:enzymology* / Q000473:pathology; D004817:Epidermis / Q000196:embryology / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D004950:Esterases / Q000378:metabolism*; D006801:Humans; D006867:Hydrolases / Q000378:metabolism; D017490:Ichthyosis, Lamellar / Q000201:enzymology / Q000473:pathology; D015603:Keratinocytes / Q000166:cytology* / Q000201:enzymology*; D008049:Lipase / Q000172:deficiency / Q000378:metabolism*; D050356:Lipid Metabolism; D008099:Liver / Q000166:cytology / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D015854:Up-Regulation; D021601:trans-Golgi Network / Q000201:enzymology
D000906:Antibodies; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; C439972:ABHD5 protein, human; C492986:Abhd5 protein, mouse; D006867:Hydrolases; D004950:Esterases; D008049:Lipase