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OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity
OTULIN is a deubiquitinase that specifically cleaves linear ubiquitin chains. Here we demonstrate that the ablation of Otulin selectively in keratinocytes causes inflammatory skin lesions that develop into verrucous carcinomas. Genetic deletion of Tnfr1, knockin expression of kinase-inactive Ripk1 o...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501048/ https://www.ncbi.nlm.nih.gov/pubmed/34625556 http://dx.doi.org/10.1038/s41467-021-25944-2 |
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author | Hoste, Esther Lecomte, Kim Annusver, Karl Vandamme, Niels Roels, Jana Maschalidi, Sophia Verboom, Lien Vikkula, Hanna-Kaisa Sze, Mozes Van Hove, Lisette Verstaen, Kevin Martens, Arne Hochepied, Tino Saeys, Yvan Ravichandran, Kodi Kasper, Maria van Loo, Geert |
author_facet | Hoste, Esther Lecomte, Kim Annusver, Karl Vandamme, Niels Roels, Jana Maschalidi, Sophia Verboom, Lien Vikkula, Hanna-Kaisa Sze, Mozes Van Hove, Lisette Verstaen, Kevin Martens, Arne Hochepied, Tino Saeys, Yvan Ravichandran, Kodi Kasper, Maria van Loo, Geert |
author_sort | Hoste, Esther |
collection | PubMed |
description | OTULIN is a deubiquitinase that specifically cleaves linear ubiquitin chains. Here we demonstrate that the ablation of Otulin selectively in keratinocytes causes inflammatory skin lesions that develop into verrucous carcinomas. Genetic deletion of Tnfr1, knockin expression of kinase-inactive Ripk1 or keratinocyte-specific deletion of Fadd and Mlkl completely rescues mice with OTULIN deficiency from dermatitis and tumorigenesis, thereby identifying keratinocyte cell death as the driving force for inflammation. Single-cell RNA-sequencing comparing non-lesional and lesional skin reveals changes in epidermal stem cell identity in OTULIN-deficient keratinocytes prior to substantial immune cell infiltration. Keratinocytes lacking OTULIN display a type-1 interferon and IL-1β response signature, and genetic or pharmacologic inhibition of these cytokines partially inhibits skin inflammation. Finally, expression of a hypomorphic mutant Otulin allele, previously shown to cause OTULIN-related autoinflammatory syndrome in humans, induces a similar inflammatory phenotype, thus supporting the importance of OTULIN for restraining skin inflammation and maintaining immune homeostasis. |
format | Online Article Text |
id | pubmed-8501048 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-85010482021-10-22 OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity Hoste, Esther Lecomte, Kim Annusver, Karl Vandamme, Niels Roels, Jana Maschalidi, Sophia Verboom, Lien Vikkula, Hanna-Kaisa Sze, Mozes Van Hove, Lisette Verstaen, Kevin Martens, Arne Hochepied, Tino Saeys, Yvan Ravichandran, Kodi Kasper, Maria van Loo, Geert Nat Commun Article OTULIN is a deubiquitinase that specifically cleaves linear ubiquitin chains. Here we demonstrate that the ablation of Otulin selectively in keratinocytes causes inflammatory skin lesions that develop into verrucous carcinomas. Genetic deletion of Tnfr1, knockin expression of kinase-inactive Ripk1 or keratinocyte-specific deletion of Fadd and Mlkl completely rescues mice with OTULIN deficiency from dermatitis and tumorigenesis, thereby identifying keratinocyte cell death as the driving force for inflammation. Single-cell RNA-sequencing comparing non-lesional and lesional skin reveals changes in epidermal stem cell identity in OTULIN-deficient keratinocytes prior to substantial immune cell infiltration. Keratinocytes lacking OTULIN display a type-1 interferon and IL-1β response signature, and genetic or pharmacologic inhibition of these cytokines partially inhibits skin inflammation. Finally, expression of a hypomorphic mutant Otulin allele, previously shown to cause OTULIN-related autoinflammatory syndrome in humans, induces a similar inflammatory phenotype, thus supporting the importance of OTULIN for restraining skin inflammation and maintaining immune homeostasis. Nature Publishing Group UK 2021-10-08 /pmc/articles/PMC8501048/ /pubmed/34625556 http://dx.doi.org/10.1038/s41467-021-25944-2 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Hoste, Esther Lecomte, Kim Annusver, Karl Vandamme, Niels Roels, Jana Maschalidi, Sophia Verboom, Lien Vikkula, Hanna-Kaisa Sze, Mozes Van Hove, Lisette Verstaen, Kevin Martens, Arne Hochepied, Tino Saeys, Yvan Ravichandran, Kodi Kasper, Maria van Loo, Geert OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity |
title | OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity |
title_full | OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity |
title_fullStr | OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity |
title_full_unstemmed | OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity |
title_short | OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity |
title_sort | otulin maintains skin homeostasis by controlling keratinocyte death and stem cell identity |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8501048/ https://www.ncbi.nlm.nih.gov/pubmed/34625556 http://dx.doi.org/10.1038/s41467-021-25944-2 |
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