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Peer-reviewedCC BYScience Advances

Canonical Wnt induction by OTULIN prevents keratinocyte death and skin inflammation

  • Kim Lecomte1,2,3
  • Pieter Hertens1,2
  • Virginie Wylleman1,2
  • Annagiada Toniolo1,2,3
  • Febe Roelandt1,2,3
  • Fleur Boone1,2
  • Maarten Ciers1,2
  • Lien Verboom1,2
  • Katrien Staes1,2
  • Geert van Loo1,2,3
  • Esther Hoste1,2,3
  1. 1VIB Center for Inflammation Research, 9052 Ghent, Belgium.
  2. 2Department of Biomedical Molecular Biology, Ghent University, 9052 Ghent, Belgium.
  3. 3Cancer Research Institute Ghent (CRIG), Ghent, Belgium.
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Abstract

gene, encoding a deubiquitinase with exclusive specificity for linear ubiquitin chains, cause a severe multiorgan autoinflammatory condition involving the skin. Mice lacking OTULIN selectively in keratinocytes develop inflamed skin lesions that progress into squamous tumors, a phenotype driven by excessive tumor necrosis factor (TNF)-induced cell death. Previous studies suggest a role for OTULIN in mediating Wnt signaling during development, but the physiological relevance of this association is unknown. Here, we show that OTULIN promotes Wnt signaling in keratinocytes by regulating the linear ubiquitination status of β-catenin. Stabilization of β-catenin in OTULIN-deficient keratinocytes prevents progressive skin inflammation in prophylactic and therapeutic settings by blocking keratinocyte death. We demonstrate that OTULIN prevents proteasomal degradation of β-catenin in cultured keratinocytes. Reduced Wnt signaling in OTULIN-deficient keratinocytes leads to degradation of TCF3/4, an essential survival factor for keratinocytes. Collectively, our data identify OTULIN's linear deubiquitination activity as a key regulator of epithelial cell viability, not only by preventing cell death downstream of TNF, but also by promoting canonical Wnt signaling.

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Cite

BibTeXRIS
BibTeX
@article{lecomte2026canonical,
  title = {{Canonical Wnt induction by OTULIN prevents keratinocyte death and skin inflammation}},
  author = {Kim Lecomte and Pieter Hertens and Virginie Wylleman and Annagiada Toniolo and Febe Roelandt and Fleur Boone and Maarten Ciers and Lien Verboom and Katrien Staes and Geert van Loo and Esther Hoste},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.adz0181},
  url = {https://www.science.org/doi/10.1126/sciadv.adz0181},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Canonical Wnt induction by OTULIN prevents keratinocyte death and skin inflammation
AU  - Kim Lecomte
AU  - Pieter Hertens
AU  - Virginie Wylleman
AU  - Annagiada Toniolo
AU  - Febe Roelandt
AU  - Fleur Boone
AU  - Maarten Ciers
AU  - Lien Verboom
AU  - Katrien Staes
AU  - Geert van Loo
AU  - Esther Hoste
PY  - 2026
DA  - 2026/10/09
JO  - Science Advances
DO  - 10.1126/sciadv.adz0181
UR  - https://www.science.org/doi/10.1126/sciadv.adz0181
AB  - gene, encoding a deubiquitinase with exclusive specificity for linear ubiquitin chains, cause a severe multiorgan autoinflammatory condition involving the skin. Mice lacking OTULIN selectively in keratinocytes develop inflamed skin lesions that progress into squamous tumors, a phenotype driven by excessive tumor necrosis factor (TNF)-induced cell death. Previous studies suggest a role for OTULIN in mediating Wnt signaling during development, but the physiological relevance of this association is unknown. Here, we show that OTULIN promotes Wnt signaling in keratinocytes by regulating the linear ubiquitination status of β-catenin. Stabilization of β-catenin in OTULIN-deficient keratinocytes prevents progressive skin inflammation in prophylactic and therapeutic settings by blocking keratinocyte death. We demonstrate that OTULIN prevents proteasomal degradation of β-catenin in cultured keratinocytes. Reduced Wnt signaling in OTULIN-deficient keratinocytes leads to degradation of TCF3/4, an essential survival factor for keratinocytes. Collectively, our data identify OTULIN's linear deubiquitination activity as a key regulator of epithelial cell viability, not only by preventing cell death downstream of TNF, but also by promoting canonical Wnt signaling.
SN  - 2375-2548
ER  -