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OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity

Author

Listed:
  • Esther Hoste

    (VIB Center for Inflammation Research
    Ghent University
    Cancer Research Institute Ghent (CRIG))

  • Kim Lecomte

    (VIB Center for Inflammation Research
    Ghent University)

  • Karl Annusver

    (Karolinska Institutet)

  • Niels Vandamme

    (VIB Center for Inflammation Research
    Computer Sciences and Statistics, Ghent University)

  • Jana Roels

    (VIB Center for Inflammation Research
    Computer Sciences and Statistics, Ghent University)

  • Sophia Maschalidi

    (VIB Center for Inflammation Research
    Ghent University)

  • Lien Verboom

    (VIB Center for Inflammation Research
    Ghent University)

  • Hanna-Kaisa Vikkula

    (VIB Center for Inflammation Research
    Ghent University)

  • Mozes Sze

    (VIB Center for Inflammation Research
    Ghent University)

  • Lisette Van Hove

    (VIB Center for Inflammation Research
    Ghent University)

  • Kevin Verstaen

    (VIB Center for Inflammation Research
    Computer Sciences and Statistics, Ghent University)

  • Arne Martens

    (VIB Center for Inflammation Research
    Ghent University)

  • Tino Hochepied

    (VIB Center for Inflammation Research
    Ghent University)

  • Yvan Saeys

    (VIB Center for Inflammation Research
    Computer Sciences and Statistics, Ghent University)

  • Kodi Ravichandran

    (VIB Center for Inflammation Research
    Ghent University
    University of Virginia)

  • Maria Kasper

    (Karolinska Institutet)

  • Geert van Loo

    (VIB Center for Inflammation Research
    Ghent University
    Cancer Research Institute Ghent (CRIG))

Abstract

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.

Suggested Citation

  • Esther Hoste & Kim Lecomte & Karl Annusver & Niels Vandamme & Jana Roels & Sophia Maschalidi & Lien Verboom & Hanna-Kaisa Vikkula & Mozes Sze & Lisette Van Hove & Kevin Verstaen & Arne Martens & Tino , 2021. "OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-25944-2
    DOI: 10.1038/s41467-021-25944-2
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    References listed on IDEAS

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