TY - JOUR
T1 - OTULIN maintains skin homeostasis by controlling keratinocyte death and stem cell identity
AU - Hoste, Esther
AU - Lecomte, Kim
AU - Annusver, Karl
AU - Vandamme, Niels
AU - Roels, Jana
AU - Maschalidi, Sophia
AU - Verboom, Lien
AU - Vikkula, Hanna Kaisa
AU - Sze, Mozes
AU - Van Hove, Lisette
AU - Verstaen, Kevin
AU - Martens, Arne
AU - Hochepied, Tino
AU - Saeys, Yvan
AU - Ravichandran, Kodi
AU - Kasper, Maria
AU - van Loo, Geert
N1 - Funding Information:
We thank the EUCOMM Consortium for Otulin-targeted ES cells, Manolis Pasparakis for providing RIPK1D138N mice, Vishva Dixit and Genentech for providing RIPK3−/− mice, and Alexander Warren and James Murphy (The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia) for the use of floxed Mlkl mice. We thank Sofie De Schepper for pathological assessment of ΔKerOTULIN mice, and Laetitia Bellen, Dimitri Huygebaert and Dieter Vanhede for animal care. We acknowledge helpful input from Jonathan Maelfait and the VIB BioImaging Core, the VIB Nucleomics Core, and the VIB Flowcore for technical assistance, and all members of the van Loo lab for suggestions and discussions. E.H. is supported by an FWO postdoctoral fellowship and a CRIG Young-Investigator grant. A.M. is supported by an FWO postdoctoral fellowship, L.v.H and L.V. are supported by an FWO FR fellowship. K.R. holds an Odysseus Grant and ERC Advanced grant. Research in the van Loo lab is financed by research grants from the FWO, Stichting Tegen Kanker, the Charcot Foundation, Kom op Tegen Kanker and the “Concerted Research Actions” (GOA) of the Ghent University.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12/1
Y1 - 2021/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85116778452&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-25944-2
DO - 10.1038/s41467-021-25944-2
M3 - Article
C2 - 34625556
AN - SCOPUS:85116778452
SN - 2041-1723
VL - 12
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5913
ER -