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

Esther Hoste (UGent) , Kim Lecomte (UGent) , Karl Annusver, Niels Vandamme (UGent) , Jana Roels (UGent) , Sophia Maschalidi (UGent) , Lien Verboom (UGent) , Hanna-Kaisa Vikkula (UGent) , Mozes Sze (UGent) , Lisette Van Hove (UGent) , et al.
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Abstract
OTULIN is a deubiquitinase for linear ubiquitin chains. Here the authors show, using genetic mouse models and single-cell RNA-sequencing, that deficiency of OTULIN in keratinocytes causes skin inflammation and verrucous carcinoma via the induction of keratinocyte death, thereby implicating a function of OTULIN in keratinocyte homeostasis. 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-1 beta 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.
Keywords
NF-KAPPA-B, LINEAR UBIQUITIN, INFLAMMATION, RECEPTOR, SHARPIN, MICE, NECROPTOSIS, IL-1, DEFICIENT, MUTATIONS

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MLA
Hoste, Esther, et al. “OTULIN Maintains Skin Homeostasis by Controlling Keratinocyte Death and Stem Cell Identity.” NATURE COMMUNICATIONS, vol. 12, no. 1, 2021, doi:10.1038/s41467-021-25944-2.
APA
Hoste, E., Lecomte, K., Annusver, K., Vandamme, N., Roels, J., Maschalidi, S., … van Loo, G. (2021). OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity. NATURE COMMUNICATIONS, 12(1). https://doi.org/10.1038/s41467-021-25944-2
Chicago author-date
Hoste, Esther, Kim Lecomte, Karl Annusver, Niels Vandamme, Jana Roels, Sophia Maschalidi, Lien Verboom, et al. 2021. “OTULIN Maintains Skin Homeostasis by Controlling Keratinocyte Death and Stem Cell Identity.” NATURE COMMUNICATIONS 12 (1). https://doi.org/10.1038/s41467-021-25944-2.
Chicago author-date (all authors)
Hoste, Esther, 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 Hochepied, Yvan Saeys, Kodi Ravichandran, Maria Kasper, and Geert van Loo. 2021. “OTULIN Maintains Skin Homeostasis by Controlling Keratinocyte Death and Stem Cell Identity.” NATURE COMMUNICATIONS 12 (1). doi:10.1038/s41467-021-25944-2.
Vancouver
1.
Hoste E, Lecomte K, Annusver K, Vandamme N, Roels J, Maschalidi S, et al. OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity. NATURE COMMUNICATIONS. 2021;12(1).
IEEE
[1]
E. Hoste et al., “OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity,” NATURE COMMUNICATIONS, vol. 12, no. 1, 2021.
@article{8728696,
  abstract     = {{OTULIN is a deubiquitinase for linear ubiquitin chains. Here the authors show, using genetic mouse models and single-cell RNA-sequencing, that deficiency of OTULIN in keratinocytes causes skin inflammation and verrucous carcinoma via the induction of keratinocyte death, thereby implicating a function of OTULIN in keratinocyte homeostasis. 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-1 beta 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.}},
  articleno    = {{5913}},
  author       = {{Hoste, Esther and Lecomte, Kim and Annusver, Karl and Vandamme, Niels and Roels, Jana and Maschalidi, Sophia and Verboom, Lien and Vikkula, Hanna-Kaisa and Sze, Mozes and Van Hove, Lisette and Verstaen, Kevin and Martens, Arne and Hochepied, Tino and Saeys, Yvan and Ravichandran, Kodi and Kasper, Maria and van Loo, Geert}},
  issn         = {{2041-1723}},
  journal      = {{NATURE COMMUNICATIONS}},
  keywords     = {{NF-KAPPA-B,LINEAR UBIQUITIN,INFLAMMATION,RECEPTOR,SHARPIN,MICE,NECROPTOSIS,IL-1,DEFICIENT,MUTATIONS}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{16}},
  title        = {{OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity}},
  url          = {{http://dx.doi.org/10.1038/s41467-021-25944-2}},
  volume       = {{12}},
  year         = {{2021}},
}

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