OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice

Hannah Schünke, Ulrike Göbel, Ivan Dikic and Manolis Pasparakis ()
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Hannah Schünke: Institute for Genetics, University of Cologne
Ulrike Göbel: Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne
Ivan Dikic: Institute of Biochemistry II, Goethe-Universität Frankfurt am Main, Buchmann Institute for Molecular Life Sciences
Manolis Pasparakis: Institute for Genetics, University of Cologne

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Linear ubiquitination regulates inflammatory and cell death signalling. Deficiency of the linear ubiquitin chain-specific deubiquitinase, OTULIN, causes OTULIN-related autoinflammatory syndrome (ORAS), a systemic inflammatory pathology affecting multiple organs including the skin. Here we show that mice with epidermis-specific OTULIN deficiency (OTULINE-KO) develop inflammatory skin lesions that are driven by TNFR1 signalling in keratinocytes and require RIPK1 kinase activity. OTULINE-KO mice lacking RIPK3 or MLKL have only very mild skin inflammation, implicating necroptosis as an important etiological mediator. Moreover, combined loss of RIPK3 and FADD fully prevents skin lesion development, showing that apoptosis also contributes to skin inflammation in a redundant function with necroptosis. Finally, MyD88 deficiency suppresses skin lesion development in OTULINE-KO mice, suggesting that toll-like receptor and/or IL-1 signalling are involved in mediating skin inflammation. Thus, OTULIN maintains homeostasis and prevents inflammation in the skin by inhibiting TNFR1-mediated, RIPK1 kinase activity-dependent keratinocyte death and primarily necroptosis.

Date: 2021
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DOI: 10.1038/s41467-021-25945-1

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