title: Lce1 Family Members Are Nrf2-Target Genes that Are Induced to Compensate for the Loss of Loricrin.
abstract: Loricrin is a major component of the cornified cell envelope, a highly insoluble structure composed of covalently cross-linked proteins. Although loricrin knockout mice only exhibit a mild transient phenotype at birth, they show a marked delay in the formation of an epidermal barrier in utero. We recently discovered that induction of a compensatory response to repair the defective barrier is initiated by amniotic fluid via activation of NF-E2-related factor 2 and identified Sprr2d and Sprr2h as direct transcriptional targets. Proteomic analysis suggested that other proteins were also incorporated into the loricrin knockout cell envelope, in addition to the small proline rich proteins. Here we present evidence suggesting that the late cornified envelope 1 proteins are also compensatory components as determined by their localization within the loricrin knockout cell envelope via immunoelectron microscopy. We also demonstrate that late cornified envelope 1 genes are upregulated at the transcriptional level in loricrin knockout mouse skin and confirm that late cornified envelope 1 genes are transcriptional targets of NRF2. Our present study further highlights the complexity and importance of a compensatory mechanism that evolved in terrestrial animals to ensure the formation of a functional epidermal barrier.
authors.affiliation: Department of Dermatology and Charles C. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Ishitsuka
authors.affiliation: Department of Dermatology and Charles C. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Huebner
authors.affiliation: Department of Environmental Toxicology, University of California, Davis, California, USA.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Rice
authors.affiliation: Department of Dermatology and Charles C. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Koch
authors.affiliation: Ted Pella, Life Sciences, Redding, California, USA.
authors.forename: Vladislav V
authors.initials: VV
authors.lastname: Speransky
authors.affiliation: Laboratory of Structural Biology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Alasdair C
authors.initials: AC
authors.lastname: Steven
authors.affiliation: Department of Dermatology and Charles C. Gates Center for Regenerative Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA. Electronic address: dennis.roop@ucdenver.edu.
authors.forename: Dennis R
authors.initials: DR
authors.lastname: Roop
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D055233:Cornified Envelope Proline-Rich Proteins / Q000235:genetics / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism*; D000072019:Kelch-Like ECH-Associated Protein 1 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D016253:Microscopy, Immunoelectron; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D040901:Proteomics; D019076:Transgenes; D015854:Up-Regulation
chemical_list: D055233:Cornified Envelope Proline-Rich Proteins; C117301:Keap1 protein, mouse; D000072019:Kelch-Like ECH-Associated Protein 1; D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; C491983:Sprr2d protein, mouse; C491980:Sprr2h protein, mouse; C064554:loricrin