LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis

Peltzer, Nieves; Darding, Maurice; Montinaro, Antonella; Dráber, Peter; Draberova, Helena; Kupka, Sebastian; Rieser, Eva; Fisher, Amanda; Hutchinson, J. Ciaran; Taraborrelli, Lucia; Hartwig, Torsten; Lafont, Élodie; Haas, Tobias; Shimizu, Yutaka; Böiers, Charlotta; Sarr, Aida; Rickard, James A; Álvarez-Díaz, Silvia; Ashworth, Michael; Beal, Allison M.; Enver, Tariq; Bertin, John; Kaiser, William J.; Strasser, Andreas; Silke, John; Bouillet, Philippe; Walczak, Henning

doi:10.1038/s41586-018-0064-8

Cited by 187 publications

(214 citation statements)

References 30 publications

Supporting

Mentioning

197

Contrasting

Order By: Relevance

“…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%

“…We tested whether OTULIN G281R ORAS fibroblasts were sensitised to TNF-induced cell death. This is in contrast to LUBAC-deficient cells (Gerlach et al, 2011;Ikeda et al, 2011;Peltzer et al, 2014Peltzer et al, , 2018 or cells expressing inactive OTULIN C129A (Heger et al, 2018), which are all sensitive to cell death induced by TNF alone. This is in contrast to LUBAC-deficient cells (Gerlach et al, 2011;Ikeda et al, 2011;Peltzer et al, 2014Peltzer et al, , 2018 or cells expressing inactive OTULIN C129A (Heger et al, 2018), which are all sensitive to cell death induced by TNF alone.…”

Section: Otulin Deficiency Sensitises Fibroblasts and Monocytes To Tnmentioning

confidence: 88%

“…Dysregulation of TNF-induced NF-jB activation in various tissues and cell types can result in inflammation due to increased cell death (Pasparakis, 2009) Boisson et al, 2012Boisson et al, , 2015, leading to TNF-R1-dependent induction of (mainly) TRADD-, FADD-and caspase-8-dependent apoptosis (Gerlach et al, 2011;Ikeda et al, 2011;Peltzer et al, 2014Peltzer et al, , 2018, which is the main driver of inflammation (Kumari et al, 2014;Rickard et al, 2014). Additionally, knock-in mice expressing catalytically inactive OTULIN C129A die mid-gestation (~E10.5) due to aberrant cell death (Heger et al, 2018), similar to HOIP-or HOIL-1-deficient mice .…”

Section: Otulin Deficiency Sensitises Fibroblasts and Monocytes To Tnmentioning

confidence: 99%

“…However, for TNF-R1, it can also lead to cell death via formation of a TRADD-, FADD-, RIPK1/3-and caspase-8-containing death-inducing complex, complex-II (Fuchs & Steller, 2015;Kupka et al, 2016b). In the absence of LUBAC, TNF-mediated signalling is shifted from NF-jB activation towards induction of cell death via complex-II (Haas et al, 2009;Tokunaga et al, 2009;Gerlach et al, 2011;Ikeda et al, 2011;Peltzer et al, 2014Peltzer et al, , 2018. In the absence of LUBAC, TNF-mediated signalling is shifted from NF-jB activation towards induction of cell death via complex-II (Haas et al, 2009;Tokunaga et al, 2009;Gerlach et al, 2011;Ikeda et al, 2011;Peltzer et al, 2014Peltzer et al, , 2018.…”

Section: Introductionmentioning

confidence: 99%

“…Recent research has shown that M1-linked Ub chains are key in determining the fate of a cell upon TNF stimulation. In the absence of LUBAC, TNF-mediated signalling is shifted from NF-jB activation towards induction of cell death via complex-II (Haas et al, 2009;Tokunaga et al, 2009;Gerlach et al, 2011;Ikeda et al, 2011;Peltzer et al, 2014Peltzer et al, , 2018. Mouse experiments have shown that the resulting TNF-induced cell death can be highly inflammatory as genetic ablation of LUBAC components leads to multi-organ inflammation (HogenEsch et al, 1993;Seymour et al, 2007;Gerlach et al, 2011;Ikeda et al, 2011;Tokunaga et al, 2011), in large part caused by TNF-induced cell death (Kumari et al, 2014;Rickard et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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

et al. 2019

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 80%

Section: Otulin Deficiency Sensitises Fibroblasts and Monocytes To Tnmentioning

confidence: 88%

Section: Otulin Deficiency Sensitises Fibroblasts and Monocytes To Tnmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

et al. 2019

View full text Add to dashboard Cite

show abstract

Deubiquitinase USP19 modulates apoptotic calcium release and endoplasmic reticulum stress by deubiquitinating BAG6 in triple negative breast cancer

Zhang,

Chen,

Qian

et al. 2023

Clinical & Translational Med

View full text Add to dashboard Cite

BackgroundTriple‐negative breast cancer (TNBC), a heterogeneous subtype of breast cancer (BC), had poor prognosis. Endoplasmic reticulum (ER) stress was responsible for cellular processes and played a crucial role in the cell function. ER stress is a complex and dynamic process that can induce abnormal apoptosis and death. However, the underlying mechanism of ER stress involved in TNBC is not well defined.MethodsWe identified ubiquitin‐specific protease 19 (USP19) as a TNBC negative regulator for further investigation. The effects of USP19 on BC proliferation were assessed in vitro using proliferation test and cell‐cycle assays, while the effects in vivo were examined using a mouse tumorigenicity model. Through in vitro flow cytometric analyses and in vivo TUNEL assays, cell apoptosis was assessed. Proteomics was used to examine the proteins that interact with USP19.ResultsMultiple in vitro and in vivo tests showed that USP19 decreases TNBC cell growth while increasing apoptosis. Then, we demonstrated that USP19 interacts with deubiquitinates and subsequently stabilises family molecular chaperone regulator 6 (BAG6). BAG6 can boost B‐cell lymphoma 2 (BCL2) ubiquitination and degradation, thereby raising ER calcium (Ca2+) levels and causing ER stress. We also found that the N6‐methyladenosine (m6A) “writer” methyltransferase‐like 14 (METTL14) increased global m6A modification.ConclusionsOur study reveals that USP19 elevates the intracellular Ca2+ concentration to alter ER stress via regulation of BAG6 and BCL2 stability and may be a viable therapeutic target for TNBC therapy.

show abstract

The pathological features of regulated necrosis

Tonnus

Meyer

Paliege

et al. 2019

The Journal of Pathology

134

View full text Add to dashboard Cite

Necrosis of a cell is defined by the loss of its plasma membrane integrity. Morphologically, necrosis occurs in several forms such as coagulative necrosis, colliquative necrosis, caseating necrosis, fibrinoid necrosis, and others. Biochemically, necrosis was demonstrated to represent a number of genetically determined signalling pathways. These include (i) kinase-mediated necroptosis, which depends on receptor interacting protein kinase 3 (RIPK3)-mediated phosphorylation of the pseudokinase mixed lineage kinase domain like (MLKL); (ii) gasdermin-mediated necrosis downstream of inflammasomes, also referred to as pyroptosis; and (iii) an iron-catalysed mechanism of highly specific lipid peroxidation named ferroptosis. Given the molecular understanding of the nature of these pathways, specific antibodies may allow direct detection of regulated necrosis and correlation with morphological features. Necroptosis can be specifically detected by immunohistochemistry and immunofluorescence employing antibodies to phosphorylated MLKL. Likewise, it is possible to generate cleavage-specific antibodies against epitopes in gasdermin protein family members. In ferroptosis, however, specific detection requires quantification of oxidative lipids by mass spectrometry (oxylipidomics). Together with classical cell death markers, such as TUNEL staining and detection of cleaved caspase-3 in apoptotic cells, the extension of the arsenal of necrosis markers will allow pathological detection of specific molecular pathways rather than isolated morphological descriptions. These novel pieces of information will be extraordinarily helpful for clinicians as inhibitors of necroptosis (necrostatins), ferroptosis (ferrostatins), and inflammasomes have emerged in clinical trials. Anatomical pathologists should embrace these novel ancillary tests and the concepts behind them and test their impact on diagnostic precision, prognostication, and the prediction of response to the upcoming anti-necrotic therapies.

show abstract

LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis

Cited by 187 publications

References 30 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

Deubiquitinase USP19 modulates apoptotic calcium release and endoplasmic reticulum stress by deubiquitinating BAG6 in triple negative breast cancer

The pathological features of regulated necrosis

Contact Info

Product

Resources

About