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

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.

Cell Death-Related Ubiquitin Modifications in Inflammatory Syndromes: From Mice to Men

“…This would in turn favour complex-II formation and cell death. This scenario was later confirmed by reports showing that OTULIN deletion in the liver causes TNFR1-driven, apoptosis- and compensatory proliferation-mediated liver pathology, while OTULIN deletion in keratinocytes causes TNFR1-driven, RIPK1 kinase activity-mediated, cell death-dependent skin inflammation [ 65 , 66 ] ( Table 1 ). Of note, some OTULIN-mutant patients display signs of liver dysfunction and skin inflammation in the form of panniculitis and neutrophilic dermatosis [ 67 ].…”

Exploring the Role of Staphylococcus aureus in Inflammatory Diseases

“…S. aureus can also induce monocytes to express IL-12, an inducer of the differentiation of Th cells to Th1 [ 165 , 288 ]. In psoriasis, S. aureus infection can also be mediated by the RIPK1/RIPK3/MLKL-mediated necrotizing apoptosis of keratinocytes, and RIPK1 mediates keratinocyte death via TNF [ 256 , 289 ].…”

Deubiquitinases in cell death and inflammation

“…By diminishing LUBAC activity, OTULIN deficiency destabilizes TNF-induced complex I and promotes the formation of complex II, leading to increased cell death [ 22 , 117 , 122–124 , 127 ]. Homozygous mutations compromising OTULIN DUB activity in mice cause embryonic lethality owing to excessive cell death, particularly among endothelial cells [ 22 , 128 ].…”

“…Embryonic lethality is prevented by the combined loss of RIPK3 and caspase-8, although the mice still die perinatally from RIPK1-dependent inflammation [ 22 ]. Systemic inactivation of OTULIN in adult mice [ 22 ], or Otulin deletion in keratinocytes [ 123 , 127 ], leads to severe inflammation that is ameliorated by Tnfr1 deletion or the combined loss of RIPK3/MLKL-dependent necroptosis and FADD/caspase-8-dependent cell death. In contrast, while Otulin deletion in hepatocytes also produces a severe inflammatory phenotype, this is not ameliorated by Tnf or Tnfr1 deletion [ 122 , 124 ], but is improved by Fadd deletion [ 124 ].…”