The interplay of <scp>IKK</scp>,<scp> NF</scp>‐κB and <scp>RIPK</scp>1 signaling in the regulation of cell death, tissue homeostasis and inflammation

Kondylis, Vangelis; Kumari, Snehlata; Vlantis, Katerina; Pasparakis, Manolis

doi:10.1111/imr.12550

Cited by 183 publications

(133 citation statements)

References 110 publications

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“…We indeed showed that TNF-mediated NF-B activity appears to be dependent on a functional Rho GTPases network, and probably on Cdc42 itself, as TNF was unable to activate NF-B in the presence of a dominant negative form of Cdc42 (data not shown). The extreme severity of the psoriasiform dermatitis exhibited by our patient is reminiscent of what is observed in mouse models of NF-B invalidation in basal keratinocytes 35,36 . For instance, a hypothesis in the nemo skin conditional knock-out mouse 37 is the interplay between mutated keratinocytes with wild type immune cells.…”

Section: Discussionsupporting

confidence: 73%

A toxic palmitoylation on Cdc42 drives a severe autoinflammatory syndrome

Bekhouche

Tourville

Ravichandran

et al. 2019

Preprint

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BackgroundAutoinflammatory diseases (AID) result from dysregulation of the first lines of innate immune responses. Recently, development of high throughput genome sequencing technology led to the rapid emergence of important knowledge in the genetic field. About 20 genes have been identified so far in monogenic forms of distinct AID. However, 70-90 % of patients with AID remain without genetic diagnosis. ObjectiveWe report the identification and characterization of a mutation in the C-terminal region of the Rho GTPase Cdc42 in a patient presenting a severe autoinflammatory phenotype. MethodsWe have analyzed the consequences of the mutation on the subcellular localization of the Cdc42 protein using imaging techniques. Molecular studies were performed using proteomic and biochemical experiments to provide mechanistic bases of the observed defects. Functional assays were also conducted using flow cytometry and cytokine production measurements. ResultsWe show that mutant Cdc42 is trapped in the Golgi apparatus due to the aberrant addition of a palmitate that both enhances the interaction of mutant Cdc42 with Golgi membranes and inhibit its extraction by GDP dissociation inhibitor (GDI), thus impairing its cytosol/membrane shuttling. At the functional level, mutant Cdc42 fails to sustain actin filaments polymerization and induces an exacerbated profile of pro-inflammatory cytokine production due to increased NF-B activation. ConclusionsOur study now provides a molecular explanation for mutations that have been identified recently in our AID patient and others in the C-terminal part of Cdc42. Mutations located in this region of Cdc42 impair the intracellular localization of Cdc42, preventing its interaction with the plasma membrane. Thus, our results definitively link mutations in the CDC42 gene to a complex immune-hemato-autoinflammatory phenotype in humans.

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Section: Discussionsupporting

confidence: 73%

A toxic palmitoylation on Cdc42 drives a severe autoinflammatory syndrome

Bekhouche

Tourville

Ravichandran

et al. 2019

Preprint

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“…However, the RIPK1 protein devoid of kinase activity appears to function as a cell death inhibitor (18,19). In this regard, RIPK1 −/− mice die perinatally, while mice that lack RIPK1, RIPK3, and caspase 8 survive, suggesting that RIPK1 controls both apoptosis and necroptosis at birth (30,31). In line with this observation, genetic silencing of RIPK1 demonstrated the specificity of Nec-1 RIPK1: Nec-1 did not protect in the absence of RIPK1.…”

Section: Discussionmentioning

confidence: 85%

TWEAK and RIPK1 mediate a second wave of cell death during AKI

Martín‐Sánchez

Fontecha‐Barriuso

Carrasco

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

120

123

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Acute kidney injury (AKI) is characterized by necrotic tubular cell death and inflammation. The TWEAK/Fn14 axis is a mediator of renal injury. Diverse pathways of regulated necrosis have recently been reported to contribute to AKI, but there are ongoing discussions on the timing or molecular regulators involved. We have now explored the cell death pathways induced by TWEAK/Fn14 activation and their relevance during AKI. In cultured tubular cells, the inflammatory cytokine TWEAK induces apoptosis in a proinflammatory environment. The default inhibitor of necroptosis [necrostatin-1 (Nec-1)] was protective, while caspase inhibition switched cell death to necroptosis. Additionally, folic acid-induced AKI in mice resulted in increased expression of Fn14 and necroptosis mediators, such as receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage domain-like protein (MLKL). Targeting necroptosis with Nec-1 or by genetic RIPK3 deficiency and genetic Fn14 ablation failed to be protective at early time points (48 h). However, a persistently high cell death rate and kidney dysfunction (72-96 h) were dependent on an intact TWEAK/Fn14 axis driving necroptosis. This was prevented by Nec-1, or MLKL, or RIPK3 deficiency and by Nec-1 stable (Nec-1s) administered before or after induction of AKI. These data suggest that initial kidney damage and cell death are amplified through recruitment of inflammation-dependent necroptosis, opening a therapeutic window to treat AKI once it is established. This may be relevant for clinical AKI, since using current diagnostic criteria, severe injury had already led to loss of renal function at diagnosis.

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“…In this complex, RIPK1 is poly-ubiquitylated by cIAPs (Bertrand et al, 2008) activating stress pathways (i.e. MAPK and NF-κB), impacting cell survival and inflammation (Kondylis et al, 2017). Nevertheless, dissociation of complex I leads to the formation of a cytosolic pro-cell death machinery (complex II) or the necrosome complex if caspases are inhibited (pharmacologically or by c-FLIP S ) or absent (Petrie et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease

Oñate

Catenaccio

Salvadores

et al. 2019

Preprint

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Parkinson's disease (PD) is the second most common neurodegenerative condition, characterized by motor impairment due to the progressive degeneration of dopaminergic neurons in the substantia nigra and depletion of dopamine release in the striatum.Accumulating evidence suggest that degeneration of axons is an early event in the disease, involving destruction programs that are independent of the survival of the cell soma. Necroptosis, a programmed cell death process, is emerging as a mediator of neuronal loss in models of neurodegenerative diseases. Here, we demonstrate activation of necroptosis in postmortem brain tissue from PD patients and in a toxin-based mouse model of the disease. Inhibition of key components of the necroptotic pathway resulted in a significant delay of 6-hydroxydopamine dependent axonal degeneration of dopaminergic and cortical neurons in vitro. Genetic ablation of necroptosis mediators MLKL and RIPK3, as well as pharmacological inhibition of RIPK1 in vivo, decreased dopaminergic neuron degeneration, improving motor performance. Together, these findings suggest that axonal degeneration in PD is mediated by the necroptosis machinery, a process here referred to as necroaxoptosis, a druggable pathway to target dopaminergic neuronal loss.

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The interplay of IKK, NF‐κB and RIPK1 signaling in the regulation of cell death, tissue homeostasis and inflammation

Cited by 183 publications

References 110 publications

A toxic palmitoylation on Cdc42 drives a severe autoinflammatory syndrome

A toxic palmitoylation on Cdc42 drives a severe autoinflammatory syndrome

TWEAK and RIPK1 mediate a second wave of cell death during AKI

The necroptosis machinery mediates axonal degeneration in a model of Parkinson disease

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