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

Spörrer, Marina; Prochnicki, Ania; C.Tölle, Regine; Nyström, Alexander; Esser, Philipp R.; Homberg, Melanie; Athanasiou, Ioannis; Zingkou, Eleni; Schillinga, Achim; Gerum, Richard; Thievessen, Ingo; Winter, Lilli; Bruckner-Tuderman, Leena; Fabry, Ben; Magin, Thomas M.; Dengjel, Jörn; Schröder, Rolf; Kiritsi, Dimitra

doi:10.1016/j.ebiom.2019.04.062

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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

2019

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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