AIF-Mediated Programmed Necrosis: A Highly Orchestrated Way to Die

Boujrad, Hanan; Gubkina, Olena; Robert, N.; Krantic, Slavica; Susín, Santos A.

doi:10.4161/cc.6.21.4842

Cited by 160 publications

(125 citation statements)

References 110 publications

(170 reference statements)

Supporting

Mentioning

120

Contrasting

Unclassified

Order By: Relevance

“…However, in contrast to STS-induced PCD, MNNG treatment provokes a double Annexin V/PI(propidium iodide)-positive labeling (Figure 1a), which is indeed a hallmark of this type of PCD. 18 MNNGinduced death is also characterized by the sequential activation of calpains and BAX (Figures 1b and c). 8 Once in mitochondria, BAX provokes a mitochondrial damage that is accompanied by the release of tAIF, the truncated form of AIF, to the cytosol and nucleus (Figures 1d and e).…”

Section: Resultsmentioning

confidence: 99%

BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation

et al. 2011

View full text Add to dashboard Cite

Alkylating DNA-damage agents such as N-methyl-N 0 -nitro-N 0 -nitrosoguanidine (MNNG) trigger necroptosis, a newly defined form of programmed cell death (PCD) managed by receptor interacting protein kinases. This caspase-independent mode of cell death involves the sequential activation of poly(ADP-ribose) polymerase-1 (PARP-1), calpains, BAX and AIF, which redistributes from mitochondria to the nucleus to promote chromatinolysis. We have previously demonstrated that the BAX-mediated mitochondrial release of AIF is a critical step in MNNG-mediated necroptosis. However, the mechanism regulating BAX activation in this PCD is poorly understood. Employing mouse embryonic knockout cells, we reveal that BID controls BAX activation in AIF-mediated necroptosis. Indeed, BID is a link between calpains and BAX in this mode of cell death. Therefore, even if PARP-1 and calpains are activated after MNNG treatment, BID genetic ablation abolishes both BAX activation and necroptosis. These PCD defects are reversed by reintroducing the BID-wt cDNA into the BID À/À cells. We also demonstrate that, after MNNG treatment, BID is directly processed into tBID by calpains. In this way, calpain non-cleavable BID proteins (BID-G70A or BID-D68-71) are unable to promote BAX activation and necroptosis. Once processed, tBID localizes in the mitochondria of MNNG-treated cells, where it can facilitate BAX activation and PCD. Altogether, our data reveal that, as in caspase-dependent apoptosis, BH3-only proteins are key regulators of caspase-independent necroptosis. Cell Death and Differentiation (2012) 19, 245-256; doi:10.1038/cdd.2011.91; published online 8 July 2011When and how a cell dies is one of the essential questions to understand the biology of the cell. A cell is considered dead when the integrity of its plasma membrane is compromised, when its fragments are engulfed by an adjacent or a professional cell or when its components, including the nucleus, are fragmented. It is more complicated to outline how a cell could die. Historically, two major types of cell death have been distinguished: apoptosis, a controlled or programmed cell death (PCD), and necrosis, an uncontrolled or accidental death. 1 Cell biologists have particularly focused their attention on apoptotic PCD, helping to characterize it at both genetic and biochemical levels. 2 Fascinatingly, the use of apoptotic inhibitors or cells that are deficient in key apoptotic molecules has revealed the existence of new PCD pathways. As a consequence, active forms of cell death started to be referred to as caspase-dependent or caspase-independent. 3 More recently, it has been accepted that necrosis is more than an unregulated type of death. Indeed, a cell can use different mechanisms/pathways with underlying apoptotic or necrotic features to accomplish its proper demise. 4 The analysis of the tumor necrosis factor (TNF) signaling path has shed new light on the existence of PCD pathways with necrotic features. When TNF binds its receptor, two ways can be engaged: (i) caspase-dependent a...

show abstract

Section: Resultsmentioning

confidence: 99%

BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation

et al. 2011

View full text Add to dashboard Cite

show abstract

“…8,9 Such an acidic extracellular environment could occur under some pathological conditions including cancer and inflammation. 10,11 Necrosis has long been considered as an accidental cell death process until it has been shown that necrosis is also a well-orchestrated programmed cell death 12,13 like apoptosis. However, there was no consensus on the specific biochemical changes, as many initiators, modulators or effectors of necrosis have been described.…”

Section: Tumor Necrosis Factor (Tnf)-related Apoptosis Inducing Liganmentioning

confidence: 99%

TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation

et al. 2012

View full text Add to dashboard Cite

Although TRAIL (tumor necrosis factor (TNF)-related apoptosis inducing ligand) is a well-known apoptosis inducer, we have previously demonstrated that acidic extracellular pH (pHe) switches TRAIL-induced apoptosis to regulated necrosis (or necroptosis) in human HT29 colon and HepG2 liver cancer cells. Here, we investigated the role of RIPK1 (receptor interacting protein kinase 1), RIPK3 and PARP-1 (poly (ADP-ribose) polymerase-1) in TRAIL-induced necroptosis in vitro and in concanavalin A (Con A)-induced murine hepatitis. Pretreatment of HT29 or HepG2 with pharmacological inhibitors of RIPK1 or PARP-1 (Nec-1 or PJ-34, respectively), or transient transfection with siRNAs against RIPK1 or RIPK3, inhibited both TRAILinduced necroptosis and PARP-1-dependent intracellular ATP depletion demonstrating that RIPK1 and RIPK3 were involved upstream of PARP-1 activation and ATP depletion. In the mouse model of Con A-induced hepatitis, where death of mouse hepatocytes is dependent on TRAIL and NKT (Natural Killer T) cells, PARP-1 activity was positively correlated with liver injury and hepatitis was prevented both by Nec-1 or PJ-34. These data provide new insights into TRAIL-induced necroptosis with PARP-1 being active effector downstream of RIPK1/RIPK3 initiators and suggest that pharmacological inhibitors of RIPKs and PARP-1 could be new treatment options for immune-mediated hepatitis.

show abstract

“…14 Finally, necroptosis is characterized by the relatively smallest number of regulators. Typically, necroptosis is modulated by c-Jun N-terminal kinase (JNK), apoptosis inducing factor (AIF), death-associated protein kinase (DAPK), and reactive oxygen species, [15][16][17][18] whereas in the apoptosis-incompetent cells, necroptosis is activated by death receptors and involves the RIP1 kinase. 19 Among the various roles of PCD in maintaining the homeostasis of living organisms is its involvement in the advancement of immune responses.…”

mentioning

confidence: 99%

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

et al. 2013

View full text Add to dashboard Cite

It is recognized now that intrinsically disordered proteins (IDPs), which do not have unique 3D structures as a whole or in noticeable parts, constitute a significant fraction of any given proteome. IDPs are characterized by an astonishing structural and functional diversity that defines their ability to be universal regulators of various cellular pathways. Programmed cell death (PCD) is one of the most intricate cellular processes where the cell uses specialized cellular machinery and intracellular programs to kill itself. This cell-suicide mechanism enables metazoans to control cell numbers and to eliminate cells that threaten the animal's survival. PCD includes several specific modules, such as apoptosis, autophagy, and programmed necrosis (necroptosis). These modules are not only tightly regulated but also intimately interconnected and are jointly controlled via a complex set of protein-protein interactions. To understand the role of the intrinsic disorder in controlling and regulating the PCD, several large sets of PCD-related proteins across 28 species were analyzed using a wide array of modern bioinformatics tools. This study indicates that the intrinsic disorder phenomenon has to be taken into consideration to generate a complete picture of the interconnected processes, pathways, and modules that determine the essence of the PCD. We demonstrate that proteins involved in regulation and execution of PCD possess substantial amount of intrinsic disorder. We annotate functional roles of disorder across and within apoptosis, autophagy, and necroptosis processes. Disordered regions are shown to be implemented in a number of crucial functions, such as protein-protein interactions, interactions with other partners including nucleic acids and other ligands, are enriched in post-translational modification sites, and are characterized by specific evolutionary patterns. We mapped the disorder into an integrated network of PCD pathways and into the interactomes of selected proteins that are involved in the p53-mediated apoptotic signaling pathway.

show abstract

AIF-Mediated Programmed Necrosis: A Highly Orchestrated Way to Die

Cited by 160 publications

References 110 publications

BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation

BID regulates AIF-mediated caspase-independent necroptosis by promoting BAX activation

TRAIL induces necroptosis involving RIPK1/RIPK3-dependent PARP-1 activation

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

Contact Info

Product

Resources

About