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OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice
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OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice
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Journal Article
OTULIN inhibits RIPK1-mediated keratinocyte necroptosis to prevent skin inflammation in mice
2021
Overview
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 (OTULIN
E-KO
) develop inflammatory skin lesions that are driven by TNFR1 signalling in keratinocytes and require RIPK1 kinase activity. OTULIN
E-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 OTULIN
E-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.
OTULIN is a negative regulator of linear ubiquitination, and its deficiency in human causes multi-organ inflammations including the skin. Here the authors show, by combining various genetic tools with epidermis-specific Otulin knockout mice, that Otulin suppresses skin inflammation predominantly by inhibiting RIPK1-mediated keratinocytes necroptosis.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/1
/ 13/2
/ 13/51
/ 38
/ 38/88
/ 38/91
/ 45
/ 64
/ 64/60
/ Animals
/ Dermatitis - prevention & control
/ Endopeptidases - pharmacology
/ Etiology
/ Female
/ Humanities and Social Sciences
/ Keratinocytes - drug effects
/ Kinases
/ Lesions
/ Male
/ Mice
/ Organs
/ Receptor-Interacting Protein Serine-Threonine Kinases - genetics
/ Receptor-Interacting Protein Serine-Threonine Kinases - metabolism
/ Receptors, Tumor Necrosis Factor, Type I
/ Science
