Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis
| Autor: | Mindy Tsai, Nicolas Gaudenzio, Axel Roers, See-Ying Tam, Yuko Kawakami, Pierre Chambon, Philipp Starkl, Dimitri Pirottin, Stephen J. Galli, Sophie El Abbas, Jinah Kim, Nadine Antoine, Fabrice Bureau, Oliwia W Zurek, Laurent L. Reber, Toshiaki Kawakami, Thomas Marichal, Riccardo Sibilano |
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| Přispěvatelé: | Groupe Interdisciplinaire de Génoprotéomique Appliquée (GIGA-Research), Université de Liège, Department of Pathology [Stanford], Stanford Medicine, Stanford University-Stanford University, Sean N. Parker Center for Allergy and Asthma Research [Stanford], Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Technische Universität Dresden = Dresden University of Technology (TU Dresden), Cell and Developmental Biology [San Diego], School of Biological Sciences [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Environmental Molecular Biology Laboratory (RIKEN), RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Walloon Excellence in Life sciences and BIOtechnology [Liège] (WELBIO), Stanford School of Medicine [Stanford], Department of Microbiology and Immunology [Stanford], Pistre, Karine |
| Rok vydání: | 2016 |
| Předmět: |
Keratinocytes
0301 basic medicine MESH: Guanine Nucleotide Exchange Factors / genetics [SDV]Life Sciences [q-bio] MESH: Myeloid Differentiation Factor 88 / immunology MESH: Dermatitis Contact / immunology Dermatitis Contact MESH: Mice Knockout Mice 0302 clinical medicine MESH: Humans Keratinocytes / immunology Guanine Nucleotide Exchange Factors MESH: Animals MESH: NF-kappa B / genetics Mice Knockout MESH: Dermatitis Contact / pathology integumentary system MESH: Signal Transduction / immunology MESH: Guanine Nucleotide Exchange Factors / immunology Chemistry NF-kappa B MESH: Epidermis / pathology General Medicine Atopic dermatitis Phenotype Cell biology [SDV] Life Sciences [q-bio] medicine.anatomical_structure MESH: NF-kappa B / immunology 030220 oncology & carcinogenesis MESH: Dermatitis Contact / genetics [SDV.IMM]Life Sciences [q-bio]/Immunology Female Guanine nucleotide exchange factor MESH: Signal Transduction / genetics Signal Transduction / immunology Signal transduction medicine.symptom Keratinocyte Signal Transduction Research Article [SDV.IMM] Life Sciences [q-bio]/Immunology Inflammation [SDV.BC]Life Sciences [q-bio]/Cellular Biology 03 medical and health sciences MESH: Keratinocytes / pathology medicine Animals Humans MESH: Receptors Interleukin-1 Type I / immunology MESH: Mice [SDV.BC] Life Sciences [q-bio]/Cellular Biology Allergic contact dermatitis Receptors Interleukin-1 Type I medicine.disease 030104 developmental biology Myeloid Differentiation Factor 88 Rab Epidermis MESH: Receptors Interleukin-1 Type I / genetics MESH: Female MESH: Myeloid Differentiation Factor 88 / genetics |
| Zdroj: | Journal of Clinical Investigation Journal of Clinical Investigation, 2016, 126 (12), pp.4497-4515. ⟨10.1172/JCI86359⟩ |
| ISSN: | 1558-8238 0021-9738 |
| DOI: | 10.1172/jci86359 |
| Popis: | International audience; Epidermal keratinocytes form a structural and immune barrier that is essential for skin homeostasis. However, the mechanisms that regulate epidermal barrier function are incompletely understood. Here we have found that keratinocyte-specific deletion of the gene encoding RAB guanine nucleotide exchange factor 1 (RABGEF1, also known as RABEX-5) severely impairs epidermal barrier function in mice and induces an allergic cutaneous and systemic phenotype. RABGEF1-deficient keratinocytes exhibited aberrant activation of the intrinsic IL-1R/MYD88/NF-κB signaling pathway and MYD88-dependent abnormalities in expression of structural proteins that contribute to skin barrier function. Moreover, ablation of MYD88 signaling in RABGEF1-deficient keratinocytes or deletion of Il1r1 restored skin homeostasis and prevented development of skin inflammation. We further demonstrated that epidermal RABGEF1 expression is reduced in skin lesions of humans diagnosed with either atopic dermatitis or allergic contact dermatitis as well as in an inducible mouse model of allergic dermatitis. Our findings reveal a key role for RABGEF1 in dampening keratinocyte-intrinsic MYD88 signaling and sustaining epidermal barrier function in mice, and suggest that dysregulation of RABGEF1 expression may contribute to epidermal barrier dysfunction in allergic skin disorders in mice and humans. Thus, RABGEF1-mediated regulation of IL-1R/MYD88 signaling might represent a potential therapeutic target. |
| Databáze: | OpenAIRE |
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