SDR9C7 catalyzes critical dehydrogenation of acylceramides for skin barrier formation
Takuya Takeichi, … , Alan R. Brash, Masashi Akiyama
Takuya Takeichi, … , Alan R. Brash, Masashi Akiyama
Published October 31, 2019
Citation Information: J Clin Invest. 2020;130(2):890-903. https://doi.org/10.1172/JCI130675.
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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 6

Potential modes of protein binding by covalent reactions of EOS-epoxy-enone.

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Potential modes of protein binding by covalent reactions of EOS-epoxy-en...
(A) The normal pathways of oxidation of linoleate esterified in CerEOS produces a reactive epoxy-enone that can bind to protein. (B) SDR9C7 deficiency almost abolishes protein binding and formation of the CLE and induces a major bypass shunt pathway in metabolism toward the CerEOS-triol. (C) Conversion of CerEOS via the actions of 12R-LOX, eLOX3, and SDR9C7 creates a reactive epoxy-enone moiety capable of reacting nonenzymatically to form covalent bonds with CCE proteins, thus forming the CLE. (D) Michael addition reactions of the enone moiety form reversible bonds with Cys or His residues. (E) Reaction of the epoxy-enone moiety with free amino groups forms a Schiff base that can rearrange to form irreversible bonding via pyrrole formation.