OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity.
Animals
Cell Death
/ genetics
Cytokines
/ metabolism
Endopeptidases
/ genetics
Fas-Associated Death Domain Protein
Gene Knock-In Techniques
Homeostasis
Inflammation
/ pathology
Interferon Type I
Interleukin-1beta
Keratinocytes
/ metabolism
Mice
Necroptosis
Peptide Fragments
Receptor-Interacting Protein Serine-Threonine Kinases
/ genetics
Receptors, Tumor Necrosis Factor, Type I
/ genetics
Skin
/ metabolism
Stem Cells
/ metabolism
Systems Analysis
Ubiquitin
/ metabolism
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
08 10 2021
08 10 2021
Historique:
received:
07
11
2020
accepted:
09
09
2021
entrez:
9
10
2021
pubmed:
10
10
2021
medline:
3
11
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 34625556
doi: 10.1038/s41467-021-25944-2
pii: 10.1038/s41467-021-25944-2
pmc: PMC8501048
doi:
Substances chimiques
Cytokines
0
Fadd protein, mouse
0
Fas-Associated Death Domain Protein
0
Interferon Type I
0
Interleukin-1beta
0
Peptide Fragments
0
Receptors, Tumor Necrosis Factor, Type I
0
Tnfrsf1a protein, mouse
0
Ubiquitin
0
interleukin-1beta (163-171)
106021-96-9
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
Ripk1 protein, mouse
EC 2.7.11.1
Endopeptidases
EC 3.4.-
gumby protein, mouse
EC 3.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5913Informations de copyright
© 2021. The Author(s).
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