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Treatment of keratinocytes with 4-phenylbutyrate in epidermolysis bullosa: Lessons for therapies in keratin disorders

  • Spörrer, Marina Department of Physics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  • Prochnicki, Ania Institute of Neuropathology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  • C.Tölle, Regine Department of Biology, University of Fribourg, Switzerland
  • Nyström, Alexander Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Esser, Philipp R. Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Homberg, Melanie Institute of Biology and SIKT, University of Leipzig, Leipzig, Germany
  • Athanasiou, Ioannis Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Zingkou, Eleni Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Schillinga, Achim Experimental Otolaryngology, ENT Hospital, Head and Neck Surgery, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
  • Gerum, Richard Department of Physics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  • Thievessen, Ingo Department of Physics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  • Winter, Lilli Institute of Neuropathology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  • Bruckner-Tuderman, Leena Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Fabry, Ben Department of Physics, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  • Magin, Thomas M. Institute of Biology and SIKT, University of Leipzig, Leipzig, Germany
  • Dengjel, Jörn Department of Biology, University of Fribourg, Switzerland - Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • Schröder, Rolf Institute of Neuropathology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
  • Kiritsi, Dimitra Department of Dermatology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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    2019
Published in:
  • EBioMedicine. - 2019, vol. 44, p. 502–515
English Missense mutations in keratin 5 and 14 genes cause the severe skin fragility disorder epidermolysis bullosa simplex (EBS) by collapsing of the keratin cytoskeleton into cytoplasmic protein aggregates. Despite intense efforts, no molecular therapies are available, mostly due to the complex phenotype of EBS, comprising cell fragility, diminished adhesion, skin inflammation and itch.Methods: We extensively characterized KRT5 and KRT14 mutant keratinocytes from patients with severe generalized EBS following exposure to the chemical chaperone 4-phenylbutyrate (4- PBA).Findings: 4-PBA diminished keratin aggregates within EBS cells and ameliorated their inflammatory phenotype. Chemoproteomics of 4-PBA-treated and untreated EBS cells revealed reduced IL1β expression- but also showed activation of Wnt/β-catenin and NF-kB pathways. The abundance of extracellular matrix and cytoskeletal proteins was significantly altered, coinciding with diminished keratinocyte adhesion and migration in a 4-PBA dose-dependent manner.Interpretation: Together, our study reveals a complex interplay of benefits and disadvantages that challenge the use of 4-PBA in skin fragility disorders.
Faculty
Faculté des sciences et de médecine
Department
Département de Biologie
Language
  • English
Classification
Biology
License
License undefined
Identifiers
Persistent URL
https://folia.unifr.ch/unifr/documents/308020
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