LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L

Taraborrelli, Lucia; Peltzer, Nieves; Montinaro, Antonella; Kupka, Sebastian; Rieser, Eva; Hartwig, Torsten; Sarr, Aida; Darding, Maurice; Dráber, Peter; Haas, Tobias; Akarca, Ayse U.; Marafioti, Teresa; Pasparakis, Manolis; Bertin, John; Gough, Peter J.; Bouillet, Philippe; Strasser, Andreas; Leverkus, Martin; Silke, John; Walczak, Henning

doi:10.1038/s41467-018-06155-8

Cited by 83 publications

(105 citation statements)

References 62 publications

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“…Interestingly, OTULIN-deficient THP-1 cells, which are hyper-inflammatory and hyper-signal in response to TNF (Fig 6), are also sensitive to this form of cell death, despite their normal levels of LUBAC. This bears resemblance to the dermatitis phenotypes in LUBACdeficient mice and the cell death observed in LUBAC-deficient cells (Kumari et al, 2014;Peltzer et al, 2014Peltzer et al, , 2018Rickard et al, 2014;Taraborrelli et al, 2018). Our analysis of cell death in biopsies from ORAS patient III.2 supports this notion and provides clear evidence of apoptosis in the skin of this patient at the time of an inflammatory flare.…”

Section: Discussionsupporting

confidence: 80%

“…Our analysis of cell death in biopsies from ORAS patient III.2 supports this notion and provides clear evidence of apoptosis in the skin of this patient at the time of an inflammatory flare. This bears resemblance to the dermatitis phenotypes in LUBACdeficient mice and the cell death observed in LUBAC-deficient cells (Kumari et al, 2014;Peltzer et al, 2014Peltzer et al, , 2018Rickard et al, 2014;Taraborrelli et al, 2018). However, in contrast to LUBAC deficiency where cells are sensitised to cell death induced by TNF alone, OTULIN-deficient cells need additional perturbation (i.e.…”

Section: Discussionmentioning

confidence: 60%

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OTULIN deficiency in ORAS causes cell type‐specific LUBAC degradation, dysregulated TNF signalling and cell death

et al. 2019

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The deubiquitinase OTULIN removes methionine‐1 (M1)‐linked polyubiquitin signals conjugated by the linear ubiquitin chain assembly complex (LUBAC) and is critical for preventing TNF‐driven inflammation in OTULIN‐related autoinflammatory syndrome (ORAS). Five ORAS patients have been reported, but how dysregulated M1‐linked polyubiquitin signalling causes their symptoms is unclear. Here, we report a new case of ORAS in which an OTULIN‐Gly281Arg mutation leads to reduced activity and stability in vitro and in cells. In contrast to OTULIN‐deficient monocytes, in which TNF signalling and NF‐κB activation are increased, loss of OTULIN in patient‐derived fibroblasts leads to a reduction in LUBAC levels and an impaired response to TNF. Interestingly, both patient‐derived fibroblasts and OTULIN‐deficient monocytes are sensitised to certain types of TNF‐induced death, and apoptotic cells are evident in ORAS patient skin lesions. Remarkably, haematopoietic stem cell transplantation leads to complete resolution of inflammatory symptoms, including fevers, panniculitis and diarrhoea. Therefore, haematopoietic cells are necessary for clinical manifestation of ORAS. Together, our data suggest that ORAS pathogenesis involves hyper‐inflammatory immune cells and TNF‐induced death of both leukocytes and non‐haematopoietic cells.

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Section: Discussionsupporting

confidence: 80%

Section: Discussionmentioning

confidence: 60%

OTULIN deficiency in ORAS causes cell type‐specific LUBAC degradation, dysregulated TNF signalling and cell death

et al. 2019

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“…Previous studies have demonstrated that the protective role of linear ubiquitination against RIPK1 kinase-dependent and -independent FADD-mediated apoptosis is not limited to TNFR1 signaling (Lafont et al, 2017; Taraborrelli et al, 2018), suggesting conserved regulatory mechanisms downstream of various death receptors. Since RIPK1 has already been implicated in liver pathology by regulating hepatocyte death (Kondylis and Pasparakis, 2019), we first evaluated the presence and consequence of RIPK1 kinase-dependent apoptosis of hepatocytes in our OTULIN LPC-KO mice.…”

Section: Resultsmentioning

confidence: 99%

OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis

Verboom

Martens

Priem

et al. 2019

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Inflammatory signaling pathways are tightly regulated to avoid chronic inflammation and the development of inflammatory pathologies. OTULIN is a deubiquitinating enzyme that specifically cleaves linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC), and OTULIN deficiency causes OTULIN-related autoinflammatory syndrome (ORAS) in humans. OTULIN was shown to negatively control NF-κB signaling in response to various stimuli, but also to protect cells from tumor necrosis factor (TNF)-induced apoptosis. To investigate the importance of OTULIN in liver homeostasis and pathology, we developed a novel mouse line specifically lacking OTULIN in liver parenchymal cells. These mice spontaneously develop a severe liver disease, characterized by liver inflammation, hepatocyte apoptosis and compensatory hepatocyte proliferation, leading to steatohepatitis, fibrosis and hepatocellular carcinoma (HCC). Genetic ablation of Fas-associated death domain (FADD) completely rescues the severe liver pathology, and knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) significantly protects from developing liver disease, demonstrating that death receptor-mediated apoptosis of OTULIN-deficient hepatocytes triggers disease pathogenesis in this model. Finally, we demonstrate that type I interferons contribute to disease pathogenesis in hepatocyte-specific OTULIN deficient mice. Together, our study reveals the critical importance of OTULIN in protecting hepatocytes from death, and thereby avoid development of chronic liver inflammation and HCC in mice.

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“…Aberrant caspase‐8 activity has been implicated in a variety of inflammatory diseases and, in some cases, can even drive lethality. For example, caspase‐8 drives lethal dermatitis in the absence of linear ubiquitin chain assembly complex (LUBAC; Taraborrelli et al , ), and caspase‐8 activity triggers embryonic lethality observed in Birc2 −/− Birc3 −/− mice (Zhang et al , ). Furthermore, caspase‐8‐dependent intestinal damage is a key driver for septic shock in mice (Mandal et al , ).…”

Section: Introductionmentioning

confidence: 99%

Beyond inflammasomes: emerging function of gasdermins during apoptosis and NETosis

2019

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Programmed cell death is a key mechanism involved in several biological processes ranging from development and homeostasis to immunity, where it promotes the removal of stressed, damaged, malignant or infected cells. Abnormalities in the pathways leading to initiation of cell death or removal of dead cells are consequently associated with a range of human diseases including infections, autoinflammatory disease, neurodegenerative disease and cancer. Apoptosis, pyroptosis and NETosis are three well-studied modes of cell death that were traditionally believed to be independent of one another, but emerging evidence indicates that there is extensive cross-talk between them, and that all three pathways can converge onto the activation of the same cell death effector-the pore-forming protein Gasdermin D (GSDMD). In this review, we highlight recent advances in gasdermin research, with a particular focus on the role of gasdermins in pyroptosis, NETosis and apoptosis, as well as cell type-specific consequences of gasdermin activation. In addition, we discuss controversies surrounding a related gasdermin family protein, Gasdermin E (GSDME), in mediating pyroptosis and secondary necrosis following apoptosis, chemotherapy and inflammasome activation.Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535: 111 -116

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LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L

Cited by 83 publications

References 62 publications

OTULIN deficiency in ORAS causes cell type‐specific LUBAC degradation, dysregulated TNF signalling and cell death

OTULIN deficiency in ORAS causes cell type‐specific LUBAC degradation, dysregulated TNF signalling and cell death

OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis

Beyond inflammasomes: emerging function of gasdermins during apoptosis and NETosis

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