Knockout of the Arp2/3 complex in epidermis causes a psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2
| Autor: | Metello Innocenti, Claudia Scarponi, Stefania Madonna, Rob A. van der Kammen, Hans Janssen, Iris de Rink, Cristina Albanesi, Ji Ying Song, Wim Brugman |
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| Přispěvatelé: | van der Kammen, R, Song, J, de Rink, I, Janssen, H, Madonna, S, Scarponi, C, Albanesi, C, Kerkhoven, R, Innocenti, M |
| Rok vydání: | 2017 |
| Předmět: |
Adult
Keratinocytes 0301 basic medicine Epidermi Mouse NF-E2-Related Factor 2 Arp2/3 complex macromolecular substances Filamentous actin Nrf2 Actin-Related Protein 2-3 Complex Mice 03 medical and health sciences medicine Animals Humans Psoriasis Molecular Biology Actin Cells Cultured Psoriasi Mice Knockout biology Actin remodeling Nfe2l2 Actin cytoskeleton Actins Cell biology Enzyme Activation Mice Inbred C57BL Actin Cytoskeleton Disease Models Animal 030104 developmental biology medicine.anatomical_structure Knockout mouse biology.protein Female Epidermis Keratinocyte Human Developmental Biology |
| Zdroj: | Development. |
| ISSN: | 1477-9129 0950-1991 |
| Popis: | Arp2/3 complex assembles branched actin filaments key to many cellular processes, but its organismal roles remain poorly understood. Here we employed conditional arpc4 knockout mice to study the function of the Arp2/3 complex in the epidermis. We found that depletion of the Arp2/3 complex by knockout of arpc4 results in skin abnormalities at birth that evolve into a severe psoriasis-like disease hallmarked by hyperactivation of transcription factor Nrf2. Knockout of arpc4 in cultured keratinocytes was sufficient to induce nuclear accumulation of Nrf2, upregulation of Nrf2-target genes and decreased filamentous actin levels. Furthermore, pharmacological inhibition of the Arp2/3 complex unmasked the role of branched actin filaments in Nrf2 regulation. Consistently, we unveiled that Nrf2 associates with the actin cytoskeleton in cells and binds to filamentous actin in vitro. Finally, we discovered that Arpc4 is downregulated in both human and mouse psoriatic epidermis. Thus, the Arp2/3 complex affects keratinocytes’ shape and transcriptome through an actin-based cell-autonomous mechanism that influences epidermal morphogenesis and homeostasis. |
| Databáze: | OpenAIRE |
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