Regulating the balance between necroptosis, apoptosis and inflammation by inhibitors of apoptosis proteins

Vasilikos, Lazaros; Spilgies, Lisanne M.; Knop, Janin; Wong, Wendy Wei-Lynn

doi:10.1038/icb.2016.118

Cited by 50 publications

(46 citation statements)

References 90 publications

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“…The best characterized members of the IAP family are x-linked IAP (xIAP) and cellular IAP1/2 (cIAP1/2) (Kocab and Duckett, 2016, Vasilikos et al., 2016). Smac mimetics are small compounds that are based on the IAP binding motif of Smac/Diablo (Figure 4A) and theoretically are also able to induce IAP degradation (Fulda, 2015, Fulda, 2016).…”

Section: Resultsmentioning

confidence: 99%

Necroptosis Execution Is Mediated by Plasma Membrane Nanopores Independent of Calcium

et al. 2017

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SummaryNecroptosis is a form of regulated necrosis that results in cell death and content release after plasma membrane permeabilization. However, little is known about the molecular events responsible for the disruption of the plasma membrane. Here, we find that early increase in cytosolic calcium in TNF-induced necroptosis is mediated by treatment with a Smac mimetic via the TNF/RIP1/TAK1 survival pathway. This does not require the activation of the necrosome and is dispensable for necroptosis. Necroptosis induced by the activation of TLR3/4 pathways does not trigger early calcium flux. We also demonstrate that necroptotic plasma membrane rupture is mediated by osmotic forces and membrane pores around 4 nm in diameter. This late permeabilization step represents a hallmark in necroptosis execution that is cell and treatment independent and requires the RIP1/RIP3/MLKL core. In support of this, treatment with osmoprotectants reduces cell damage in an in vivo necroptosis model of ischemia-reperfusion injury.

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Section: Resultsmentioning

confidence: 99%

Necroptosis Execution Is Mediated by Plasma Membrane Nanopores Independent of Calcium

et al. 2017

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“…The TUNEL method is one of the most widely used detection methods for apoptosis in paraffin tissue sections. 27 Our TUNEL results showed that the apoptosis rate of the rats in the 4.5 and 8.5 mg/kg exposure groups was significantly higher than that in the control group. Therefore, we believe that long-term low-dose exposure of crotonaldehyde to male rats leads to apoptosis in rat lung tissue cells.…”

Section: The Changes Of Apoptosis-related Proteinsmentioning

confidence: 63%

Apoptosis of lung cells regulated by mitochondrial signal pathway in crotonaldehyde‐induced lung injury

Wei

Zhang

et al. 2020

Environmental Toxicology

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Crotonaldehyde, a highly toxic α, β-unsaturated aldehyde, is a ubiquitous hazardous pollutant. Because of its extreme toxicity and ubiquity in all types of smoke, most current research focuses on the lung toxicity of such air pollutants. However, the specific mechanism of pulmonary toxicity caused by crotonaldehyde remains unclear, especially after long-term exposure to crotonaldehyde at low dose. Therefore, the aim of the present study is to determine whether crotonaldehyde-induced oxidative damage and inflammation promote apoptosis in rats via the mitochondrial pathway using histopathology, immunohistochemistry, biochemistry analysis and Western blot analysis. The results show that crotonaldehyde elicited oxidative damage and inflammation in rats in a concentration-dependent manner. Crotonaldehyde-induced lung injury which was confirmed by H&E, Masson's trichrome staining and TUNEL. And crotonaldehyde-induced lung cell apoptosis showed a concentration-response relationship. Immunohistochemistry and Western blot results showed that apoptotic mitochondrial signaling pathway is abnormally activated in crotonaldehyde-induced lung injury. Collectively, this study demonstrates that exposure of rats to crotonaldehyde induces lung injury by inducing apoptosis, which is related to oxidative damage and inflammation through mitochondrial pathway.

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“…Simplistically, TNF is believed to signal via the NF‐κB pathway as a default setting. When RIPK1 ubiquitylation is compromised, such as by inhibition or depletion of the E3 ubiquitin ligases, the inhibitor of apoptosis proteins (IAPs; reviewed in Vasilikos et al , 14 and Lalaoui and Brumatti, 15 ), RIPK1 can participate in death signalling. In cases where caspase‐3 and caspase‐8 activity operates, RIPK1, 16 CYLD 17 and possibly RIPK3 18 are cleaved and apoptosis prevails.…”

Section: The Necroptotic Pathwaymentioning

confidence: 99%

Insane in the membrane: a structural perspective of MLKL function in necroptosis

2017

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Necroptosis (or 'programmed necrosis') is a caspase-independent cell death pathway that operates downstream of death receptors, including Tumour Necrosis Factor Receptor-1 (TNFR1), and the Toll-like receptors, TLR3 and TLR4. Owing to its immunogenicity, necroptosis has been attributed roles in the pathogenesis of several diseases, including inflammatory bowel disease and the tissue damage arising from ischaemic-reperfusion injuries. Only over the past 7 years has the core machinery of this pathway, the receptor-interacting protein kinase-3 (RIPK3) and the pseudokinase, Mixed Lineage Kinase domain-Like (MLKL), been defined. Our current understanding of the pathway is that RIPK3-mediated phosphorylation activates cytoplasmic MLKL, which is the most terminal known effector in the pathway, leading to MLKL's oligomerisation, translocation to, and permeabilisation of, the plasma membrane. Here, we discuss the insights gleaned from structural and biophysical studies of MLKL and highlight the known unknowns surrounding MLKL's mechanism of action and activation.

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Regulating the balance between necroptosis, apoptosis and inflammation by inhibitors of apoptosis proteins

Cited by 50 publications

References 90 publications

Necroptosis Execution Is Mediated by Plasma Membrane Nanopores Independent of Calcium

Necroptosis Execution Is Mediated by Plasma Membrane Nanopores Independent of Calcium

Apoptosis of lung cells regulated by mitochondrial signal pathway in crotonaldehyde‐induced lung injury

Insane in the membrane: a structural perspective of MLKL function in necroptosis

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