Unbound Corneocyte Lipid Envelopes in 12R-Lipoxygenase Deficiency Support a Specific Role in Lipid-Protein Cross-Linking

• DOI: 10.1016/j.ajpath.2021.02.005
• Publication Date: 2021-02-17T03:50:07Z
• Authors: Jason M. Meyer; Debra Crumrine; Holm Schneider; Angela Dick; Matthias Schmuth; Robert Gruber; Franz P.W. Radner; Susanne Grond; Joan S. Wakefield; Theodora M. Mauro; Peter M. Elias
• Keywords: Keratinocytes; Male; Biomedical and clinical sciences; 572; Pyridines; Knockout; Arachidonate 12-Lipoxygenase; Medical and Health Sciences; Mice; 03 medical and health sciences; Pathology; 2.1 Biological and endogenous factors; Animals; Humans; Aetiology; Skin; Mice, Knockout; 0303 health sciences; Biomedical and Clinical Sciences; Health sciences; Ichthyosis; Proteins; Middle Aged; Lipid Metabolism; Mutation; Female; Epidermis

Loss-of-function mutations in arachidonate lipoxygenase 12B (ALOX12B) are an important cause of autosomal recessive congenital ichthyosis (ARCI). 12R-lipoxygenase (12R-LOX), the protein product of ALOX12B, has been proposed to covalently bind the corneocyte lipid envelope (CLE) to the proteinaceous corneocyte envelope, thereby providing a scaffold for the assembly of barrier-providing, mature lipid lamellae. To test this hypothesis, an in-depth ultrastructural examination of CLEs was performed in ALOX12B-/- human and Alox12b-/- mouse epidermis, extracting samples with pyridine to distinguish covalently attached CLEs from unbound (ie, noncovalently bound) CLEs. ALOX12B--/- stratum corneum contained abundant pyridine-extractable (ie, unbound) CLEs, compared with normal stratum corneum. These unbound CLEs were associated with defective post-secretory lipid processing, and were specific to 12R-LOX deficiency, because they were not observed with deficiency of the related ARCI-associated proteins, patatin-like phospholipase 1 (Pnpla1) or abhydrolase domain containing 5 (Abhd5). These results suggest that 12R-LOX contributes specifically to CLE-corneocyte envelope cross-linking, which appears to be a prerequisite for post-secretory lipid processing, and provide insights into the pathogenesis of 12R-LOX deficiency in this subtype of ARCI, as well as other conditions that display a defective CLE.