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 1

Changes in SDR9C7 expression and major changes in ceramides in the patient’s skin.

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Changes in SDR9C7 expression and major changes in ceramides in the patie...
(A) Thin shiny scales on the lower leg are observed. (B) A biopsy sample from the ichthyotic skin of the proband shows marked compact hyperkeratosis, which suggests deficiency of the intercellular lipid layers in the stratum corneum. In contrast, the stratum corneum of the normal control skin shows a basket-weave pattern. Scale bars = 20 μm. (C) Immunohistochemistry of the lesional skin with an anti–SDR9C7 antibody. The staining intensity is strongly reduced in the patient’s skin compared with the skin from a healthy control. Scale bars = 50 μm. (D and E) Total ceramide levels in tape-stripped samples of epidermis are within the normal range in the patient compared with her parents and the normal controls (n = 8). Data represent mean ± SEM. (F and G) Individual ceramide species showed minor differences in the patient’s forearm and upper arm, with the notable exception of CerEOS, 200%–280% elevated in the patient’s epidermis. (H and I) By contrast, ceramides covalently bound to protein were severely reduced in the patient’s skin compared with the parents and controls (n = 8). Data represent mean ± SEM.