SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation
Takuya Takeichi, Tetsuya Hirabayashi, Yuki Miyasaka, Akane Kawamoto, Yusuke Okuno, Shijima Taguchi, Kana Tanahashi, Chiaki Murase, Hiroyuki Takama, Kosei Tanaka, William E. Boeglin, M. Wade Calcutt, Daisuke Watanabe, Michihiro Kono, Yoshinao Muro, Junko Ishikawa, Tamio Ohno, Alan R. Brash, Masashi Akiyama
Takuya Takeichi, Tetsuya Hirabayashi, Yuki Miyasaka, Akane Kawamoto, Yusuke Okuno, Shijima Taguchi, Kana Tanahashi, Chiaki Murase, Hiroyuki Takama, Kosei Tanaka, William E. Boeglin, M. Wade Calcutt, Daisuke Watanabe, Michihiro Kono, Yoshinao Muro, Junko Ishikawa, Tamio Ohno, Alan R. Brash, Masashi Akiyama
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Research Article Dermatology

SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation

Abstract

The corneocyte lipid envelope, composed of covalently bound ceramides and fatty acids, is important to the integrity of the permeability barrier in the stratum corneum, and its absence is a prime structural defect in various skin diseases associated with defective skin barrier function. SDR9C7 encodes a short-chain dehydrogenase/reductase family 9C member 7 (SDR9C7) recently found mutated in ichthyosis. In a patient with SDR9C7 mutation and a mouse Sdr9c7-KO model, we show loss of covalent binding of epidermal ceramides to protein, a structural fault in the barrier. For reasons unresolved, protein binding requires lipoxygenase-catalyzed transformations of linoleic acid (18:2) esterified in ω-O-acylceramides. In Sdr9c7–/– epidermis, quantitative liquid chromatography–mass spectometry (LC-MS) assays revealed almost complete loss of a species of ω-O-acylceramide esterified with linoleate-9,10-trans-epoxy-11E-13-ketone; other acylceramides related to the lipoxygenase pathway were in higher abundance. Recombinant SDR9C7 catalyzed NAD+-dependent dehydrogenation of linoleate 9,10-trans-epoxy-11E-13-alcohol to the corresponding 13-ketone, while ichthyosis mutants were inactive. We propose, therefore, that the critical requirement for lipoxygenases and SDR9C7 is in producing acylceramide containing the 9,10-epoxy-11E-13-ketone, a reactive moiety known for its nonenzymatic coupling to protein. This suggests a mechanism for coupling of ceramide to protein and provides important insights into skin barrier formation and pathogenesis.

Authors

Takuya Takeichi, Tetsuya Hirabayashi, Yuki Miyasaka, Akane Kawamoto, Yusuke Okuno, Shijima Taguchi, Kana Tanahashi, Chiaki Murase, Hiroyuki Takama, Kosei Tanaka, William E. Boeglin, M. Wade Calcutt, Daisuke Watanabe, Michihiro Kono, Yoshinao Muro, Junko Ishikawa, Tamio Ohno, Alan R. Brash, Masashi Akiyama

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Figure 7

Role of SDR9C7 in the routes of ceramide oxidation leading to covalent binding to protein and formation of the CLE.

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Role of SDR9C7 in the routes of ceramide oxidation leading to covalent b...
Top: CerEOS is synthesized via ω-hydroxylation of ULCFA by CYP4F22, the coupling of ω-hydroxy-ULCFA with dihydrosphingosine by CERS3 and subsequent desaturation to form CerOS, and transacylation of linoleate from triglyceride (TG) to CerOS by PNPLA1. Middle: The linoleate in CerEOS is oxygenated by 12R-LOX to the 9R-hydroperoxide, isomerized by eLOX3 to the RRR-epoxy-alcohol, followed by dehydrogenation by SDR9C7 to form the reactive CerEOS-epoxy-enone. Last steps: Covalent coupling to protein may occur by the conventionally understood mechanism involving hydrolysis of the oxidized linoleate and binding of the resulting CerOS to protein via uncharacterized esterase and transglutaminase (TGase) enzymes (left-hand route), and/or by direct binding of CerEOS-epoxy-enone to CCE proteins thus forming covalent bonds, potentially via nonenzymatic reactions of the epoxy-enone moiety (right-hand route).