Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features

Berghe, Tom Vanden; Vanlangenakker, Nele; Parthoens, Eef; Deckers, Wies; Devos, Michaël; Festjens, Nele; Guérin, Christopher J.; Brunk, Ulf T.; Declercq, Wim; Vandenabeele, Peter

doi:10.1038/cdd.2009.184

Cited by 492 publications

(320 citation statements)

References 43 publications

(62 reference statements)

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“…It is possible that the cell death inhibitory effect of zVAD-fmk when used at increasing concentrations observed here reflects the progressive inhibition of caspases and other cysteine proteases such as calpains and cathepsins that are also targets of zVADfmk (45). In agreement with a role for cathepsins in the cell death mechanism, lysosomal membrane permeabilization was recently described as a common denominator in several necrotic death modes including necroptosis (46).…”

Section: Discussionsupporting

confidence: 59%

Identification of Small Molecule Inhibitors of Phosphatidylinositol 3-Kinase and Autophagy

Farkas

Daugaard

Jäättelä

2011

Journal of Biological Chemistry

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Macroautophagy (hereafter autophagy) is a lysosomal catabolic pathway that controls cellular homeostasis and survival. It has recently emerged as an attractive target for the treatment of a variety of degenerative diseases and cancer. The targeting of autophagy has, however, been hampered by the lack of specific small molecule inhibitors. Thus, we screened two small molecule kinase inhibitor libraries for inhibitors of rapamycin-induced autophagic flux. The three most potent inhibitors identified conferred profound inhibition of autophagic flux by inhibiting the formation of autophagosomes. Notably, the autophagy inhibitory effects of all three compounds were independent of their established kinase targets, i.e. ataxia telangiectasia mutated for KU55933, protein kinase C for Gö6976, and Janus kinase 3 for Jak3 inhibitor VI. Instead, we identified phosphatidylinositol 3-kinase (PtdIns3K) as a direct target of KU55933 and Gö6976. Importantly, and in contrast to the currently available inhibitors of autophagosome formation (e.g. 3-methyladenine), none of the three compounds inhibited the cell survival promoting class I phosphoinositide 3-kinase-Akt signaling at the concentrations required for effective autophagy inhibition. Accordingly, they proved to be valuable tools for investigations of autophagy-associated cell death and survival. Employing KU55399, we demonstrated that autophagy protects amino acid-starved cells against both apoptosis and necroptosis. Taken together, our data introduce new possibilities for the experimental study of autophagy and can form a basis for the development of clinically relevant autophagy inhibitors.Autophagy is an intracellular degradative process by which cells recycle macromolecules and organelles (1-4). In this process, cellular material is sequestered in double membrane vesicles termed autophagosomes that fuse with lysosomes to form autolysosomes, in which the cargo is exposed to acidic hydrolases. Autophagy is essential for energy homeostasis and removal of damaged organelles and protein complexes during various kinds of stresses, such as starvation, growth factor deprivation, hypoxia, and DNA damage. It is also involved in physiological processes like development, immunity, and aging as well as in various diseases including neurodegenerative disorders and cancer. Whereas autophagy clearly has a beneficial effect in preventing many degenerative disorders, its role in cancer is more complex. It can function as a tumor suppressor mechanism, and yet it can also promote tumor growth by protecting cancer cells against the hostile tumor environment and antineoplastic drugs (5, 6).The mammalian target of rapamycin complex 1 (mTORC1) 3 serine/threonine kinase integrates information on cell metabolic, growth, and stress status to regulate biosynthetic pathways and autophagy (7,8). It activates biosynthetic pathways and inhibits autophagy in response to various growth factors via MAPK/ERK and class I phosphoinositide 3-kinase (PI3K)/Aktdependent pathways. On the other hand, when the ene...

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Section: Discussionsupporting

confidence: 59%

Identification of Small Molecule Inhibitors of Phosphatidylinositol 3-Kinase and Autophagy

Farkas

Daugaard

Jäättelä

2011

Journal of Biological Chemistry

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“…Towards this, we challenged primary macrophages with pyroptosis inducers and lysosomedestabilizing agents in the presence of lysosomotropic agents. We found that the lysosomotropic agent NH 4 Cl blocked necrotic cell death mediated by LLOMe and the pyroptosis inducer LT, yet with distinct efficiencies (Fig. 1C).…”

Section: Resultsmentioning

confidence: 86%

“…1C). Significantly lower NH 4 Cl concentrations were required to block LT-induced cell death compared to LLOMe-induced cell death (Fig. 1C).…”

Section: Resultsmentioning

confidence: 99%

“…12,15 We have recently described a third form of necrotic cell death, designated as lysosome-mediated necrosis (LMN), that is characterized by lysosome rupture and broad proteolysis of cytosolic proteins. 28,35 Intriguingly, the cathepsin Bselective inhibitor, CA-074-Me, blocks not only all known forms of necrotic cell death, but also apoptotic cell death 4,21 The mechanism by which CA-074-Me blocks necrotic cell death is unclear and a major focus of this study.…”

Section: Introductionmentioning

confidence: 99%

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Distinct cathepsins control necrotic cell death mediated by pyroptosis inducers and lysosome-destabilizing agents

et al. 2015

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“…Unlike apoptosis, necrosis is described as an uncontrolled and accidental form of cell death until genetically determined, regulated processes that mediates necrotic cellular demise, which were recently identified and are now termed programmed necrosis or necroptosis 14, 15. Necroptosis shares with necrosis the fact that dying cells display the morphological features of necrosis but not of apoptosis, but is highly regulated by an intracellular protein platform 14, 16. Recent advances have shown that activation of the kinase domain of receptor‐interacting protein1 (RIP1) and the assembly of RIP1/3‐containing signalling complex (termed the necrosome) mediated necroptosis contributes to the pathogenesis in preclinical models of brain 17, 18, heart 19, 20, and kidney 21, 22 I/R injury, which can be protected by using the RIP1 kinase inhibitor necrostatin (Nec)‐1.…”

Section: Introductionmentioning

confidence: 99%

Necroptosis is a key mediator of enterocytes loss in intestinal ischaemia/reperfusion injury

Wen

Ling

Yang

et al. 2016

J Cellular Molecular Medi

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Cell death is an important biological process that is believed to have a central role in intestinal ischaemia/reperfusion (I/R) injury. While the apoptosis inhibition is pivotal in preventing intestinal I/R, how necrotic cell death is regulated remains unknown. Necroptosis represents a newly discovered form of programmed cell death that combines the features of both apoptosis and necrosis, and it has been implicated in the development of a range of inflammatory diseases. Here, we show that receptor‐interacting protein 1/3 (RIP1/3) kinase and mixed lineage kinase domain‐like protein recruitment mediates necroptosis in a rat model of ischaemic intestinal injury in vivo. Furthermore, necroptosis was specifically blocked by the RIP1 kinase inhibitor necrostatin‐1. In addition, the combined treatment of necrostatin‐1 and the pan‐caspase inhibitor Z‐VAD acted synergistically to protect against intestinal I/R injury, and these two pathways can be converted to one another when one is inhibited. In vitro, necrostatin‐1 pre‐treatment reduced the necroptotic death of oxygen‐glucose deprivation challenged intestinal epithelial cell‐6 cells, which in turn dampened the production of pro‐inflammatory cytokines (tumour necrosis factor‐α and interleukin‐1β), and suppressed high‐mobility group box‐1 (HMGB1) translocation from the nucleus to the cytoplasm and the subsequent release of HMGB1 into the supernatant, thus decreasing the activation of Toll‐like receptor 4 and the receptor for advanced glycation end products. Collectively, our study reveals a robust RIP1/RIP3‐dependent necroptosis pathway in intestinal I/R‐induced intestinal injury in vivo and in vitro and suggests that the HMGB1 signalling is highly involved in this process, making it a novel therapeutic target for acute ischaemic intestinal injury.

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Necroptosis, necrosis and secondary necrosis converge on similar cellular disintegration features

Cited by 492 publications

References 43 publications

Identification of Small Molecule Inhibitors of Phosphatidylinositol 3-Kinase and Autophagy

Identification of Small Molecule Inhibitors of Phosphatidylinositol 3-Kinase and Autophagy

Distinct cathepsins control necrotic cell death mediated by pyroptosis inducers and lysosome-destabilizing agents

Necroptosis is a key mediator of enterocytes loss in intestinal ischaemia/reperfusion injury

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