The Experts below are selected from a list of 4977 Experts worldwide ranked by ideXlab platform
Jochen H. M. Prehn - One of the best experts on this subject based on the ideXlab platform.
-
Bid Promotes K63-Linked Polyubiquitination of Tumor Necrosis Factor Receptor Associated Factor 6 (TRAF6) and Sensitizes to Mutant SOD1-Induced Proinflammatory Signaling in Microglia.
eNeuro, 2016Co-Authors: Sinéad Kinsella, Hans-georg König, Jochen H. M. PrehnAbstract:Abstract Mutations in the Superoxide dismutase (SOD1) gene contribute to motoneuron degeneration and are evident in 20% of familial ALS cases. Mutant SOD1 induces microglial activation through a stimulation of Toll-like Receptors 2 and 4 (TLR2 and TLR4). In the present study we identified the pro-apoptotic Bcl-2 family Protein Bid as a positive regulator of mutant SOD1-induced TLR – Nuclear Factor-κB (NF-κB) signalling in microglia. Bid -deficient primary mouse microglia showed reduced NF-κB signalling in response to TLR4 activation or exposure to conditioned medium derived from SOD1 G93A expressing NSC-34 cells. Attenuation of NF-κB signalling in Bid- deficient microglia was associated with lower levels of phosphorylated IKKα/β and p65, with a delayed degradation of IκBα and enhanced degradation of Peli1. Upstream of IKK, we found that Bid interacted with, and promoted the K63-linked polyubiquitination of the E3 ubiquitin ligase tumor necrosis factor (α) receptor adaptor Protein 6 (TRAF6) in microglia. Our study suggests a key role for Bid in the regulation of TLR4-NF-κB pro-inflammatory signalling during mutant SOD1-induced disease pathology. Significance Statement: Recent work suggests that many pro-apoptotic Proteins also function in other cell signalling pathways and may affect inflammatory responses. Inflammation is a hallmark of ALS disease models, and inflammation-associated markers in ALS patients are associated with more severe disease progression. Here we demonstrate that the pro-apoptotic Bcl-2 family Protein Bid plays a crucial role in mutant SOD1-induced microglial activation, and delineate a novel signal transduction pathway activated by Bid involving K63-linked polyubiquitination of the E3 ubiquitin ligase tumor necrosis factor (α) receptor adaptor Protein 6 (TRAF6) and subsequent NF-κB activation.
-
The BCL-2 family Protein Bid is critical for pro-inflammatory signaling in astrocytes.
Neurobiology of disease, 2014Co-Authors: Hans-georg König, Karen S. Coughlan, Sinéad Kinsella, Bridget Breen, Jochen H. M. PrehnAbstract:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons in the spinal cord, brainstem and motor cortex. Mutations in the superoxide dismutase 1 (SOD1) gene represent a frequent genetic determinant and recapitulate a disease phenotype similar to ALS when expressed in mice. Previous studies using SOD1(G93A) transgenic mice have suggested a paracrine mechanism of neuronal loss, in which cytokines and other toxic factors released from astroglia or microglia trigger motoneuron degeneration. Several pro-inflammatory cytokines activate death receptors and may downstream from this activate the Bcl-2 family Protein, Bid. We here sought to investigate the role of Bid in astrocyte activation and non-cell autonomous motoneuron degeneration. We found that spinal cord Bid Protein levels increased significantly during disease progression in SOD1(G93A) mice. Subsequent experiments in vitro indicated that Bid was expressed at relatively low levels in motoneurons, but was enriched in astrocytes and microglia. Bid was strongly induced in astrocytes in response to pro-inflammatory cytokines or exposure to lipopolysaccharide. Experiments in Bid-deficient astrocytes or astrocytes treated with a small molecule Bid inhibitor demonstrated that Bid was required for the efficient activation of transcription factor nuclear factor-κB in response to these pro-inflammatory stimuli. Finally, we found that conditioned medium from wild-type astrocytes, but not from Bid-deficient astrocytes, was toxic when applied to primary motoneuron cultures. Collectively, our data demonstrate a new role for the Bcl-2 family Protein Bid as a mediator of astrocyte activation during neuroinflammation, and suggest that Bid activation may contribute to non-cell autonomous motoneuron degeneration in ALS.
-
BH3-only Protein Bid is dispensable for seizure-induced neuronal death and the associated nuclear accumulation of apoptosis-inducing factor.
Journal of neurochemistry, 2010Co-Authors: Tobias Engel, Andreas Strasser, Jochen H. M. Prehn, Aurelien Caballero-caballero, Clara K. Schindler, Nikolaus Plesnila, David C. HenshallAbstract:Prolonged seizures activate members of the Bcl-2 homology domain 3-only sub-group of the Bcl-2 Protein family, which are essential for initiation of apoptosis signaling. Bid is a potent pro-apoptotic Bcl-2 homology domain 3-only Protein, which upon proteolytic activation translocates to mitochondria to promote activation of the Bax/Bak sub-group of the pro-apoptotic Bcl-2 family and thereby contributes to release of apoptogenic molecules, such as cytochrome c and possibly apoptosis-inducing factor (AIF). Bid-deficient mice have been reported to show reduced lesion volumes after ischemia and trauma in vivo but a causal role for Bid in the setting of seizure-induced neuronal death has not been investigated. In this study, we studied Bid activation following status epilepticus in mice and compared hippocampal damage between wild-type and Bid-deficient animals. Full-length Bid was detected in normal mouse hippocampus and the cleaved (activated) p15 fragment of Bid was detected shortly after status epilepticus. Bid-deficient mice underwent equivalent electrographic seizure responses during status epilepticus as wild-type animals. Hippocampal counts of degenerating neurons and surviving neuron-specific nuclear Protein-positive cells were not significantly different between wild-type and Bid-deficient mice. Additionally, nuclear translocation of AIF was not reduced in Bid-deficient compared with wild-type animals subjected to status epilepticus. The present study demonstrates that AIF is not dependent on Bid for mitochondrial release and nuclear import in this model and that while Bid is cleaved during seizure-induced neuronal death, it may be functionally redundant or even not essential.
-
Bid and Calpains cooperate to Trigger Oxaliplatin-induced Apoptosis of Cervical Carcinoma HeLa Cells
Molecular pharmacology, 2009Co-Authors: Sergio Anguissola, Barbara Köhler, Robert O'byrne, Heiko Düssmann, Mary Cannon, Frank E. Murray, Caoimhín G. Concannon, Markus Rehm, Donat Kögel, Jochen H. M. PrehnAbstract:The Bcl-2 homology 3-only Protein Bid is an important mediator of death receptor-induced apoptosis. Recent reports and this study suggest that Bid may also mediate genotoxic drug-induced apoptosis of various human cancer cells. Here, we characterized the role of Bid and the mechanism of Bid activation during oxaliplatin-induced apoptosis of HeLa cervical cancer cells. Small hairpin RNA-mediated silencing of Bid protected HeLa cells against both death receptor- and oxaliplatin-induced apoptosis. Expression of a Bid mutant in which caspase-8 cleavage site was mutated (D59A) reactivated oxaliplatin-induced apoptosis in Bid-deficient cells but failed to reactivate death receptor-induced apoptosis, suggesting that caspase-8-mediated Bid cleavage did not contribute to oxaliplatin-induced apoptosis. Overexpression of bcl-2 or treatment with the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-dl-Asp-fluoromethylketone abolished caspase-2, -8, -9, and -3 activation as well as Bid cleavage in response to oxaliplatin, suggesting that Bid cleavage occurred downstream of mitochondrial permeabilization and was predominantly mediated by caspases. We also detected an early activation of calpains in response to oxaliplatin. Calpain inhibition reduced Bid cleavage, mitochondrial depolarization, and activation of caspase-9, -3, -2, and -8 in response to oxaliplatin. Further experiments, however, suggested that Bid cleavage by calpains was not a prerequisite for oxaliplatin-induced apoptosis: single-cell imaging experiments using a yellow fluorescent Protein-Bid-cyan fluorescent Protein probe demonstrated translocation of full-length Bid to mitochondria that was insensitive to calpain or caspase inhibition. Moreover, calpain inhibition showed a potent protective effect in Bid-silenced cells. In conclusion, our data suggest that calpains and Bid act in a cooperative, but mutually independent, manner to mediate oxaliplatin-induced apoptosis of HeLa cells.
-
Neuronal apoptosis: BH3-only Proteins the real killers?
Journal of bioenergetics and biomembranes, 2004Co-Authors: Manus W. Ward, Donat Kögel, Jochen H. M. PrehnAbstract:At present there is a poor understanding of the events that lead up to neuronal apoptosis that occurs in neurodegenerative diseases and following acute ischemic episodes. Apoptosis is critical for the elimination of unwanted neurons within the developing nervous system. The Bcl-2 family of Proteins contains pro- and anti-apoptotic Proteins that regulate the mitochondrial pathway of apoptosis. There is increasing interest in a subfamily of the Bcl-2 family, the BH3-only Proteins, and their pro-apoptotic effects within neurons. Recently ischemic and seizure-induced neuronal injury has been shown to result in the activation of the BH3-only Protein, Bid. This Protein is cleaved and the truncated Protein (tBid) translocates to the mitochondria. The translocation of tBid to the mitochondria is associated with the activation of outer mitochondrial membrane Proteins Bax/Bak and the release of cytochrome C from the mitochondria. ER stress also has been implicated as a factor for the induction of apoptosis in ischemic neuronal injury. The induction of ER stress in hippocampal neurons has been shown to activate expression of bb3/PUMA, a member of the BH3-only gene family. Activation of PUMA is associated with the activation and clustering of the pro-apoptotic Bcl-2 family member Bax and the loss of cytochrome C from the mitochondria.
S Orrenius - One of the best experts on this subject based on the ideXlab platform.
-
Mitochondrial targeting of tBid/Bax: a role for the TOM complex?
Cell Death & Differentiation, 2009Co-Authors: E Norberg, B Zhivotovsky, S OrreniusAbstract:The release of pro-apoptotic Proteins from the mitochondria is a key event in cell death signaling that is regulated by Bcl-2 family Proteins. For example, cleavage of the BH3-only Protein, Bid, by multiple proteases leads to the formation of truncated Bid that, in turn, promotes the insertion/oligomerization of Bax into the mitochondrial outer membrane, resulting in pore formation and the release of Proteins residing in the intermembrane space. Bax, a monomeric Protein in the cytosol is targeted to the mitochondria by a yet unknown mechanism. Several Proteins of the outer mitochondrial membrane have been proposed to act as receptors for Bax, among them the voltage-dependent anion channel, VDAC, and the mitochondrial Protein translocase of the outer membrane, the TOM complex. Alternatively, the unique mitochondrial phospholipid, cardiolipin, has been ascribed a similar function. Here, we review recent work on the mechanisms of activation and the targeting of Bax to the mitochondria and discuss the advantages and limitations of the methods used to study this process.
-
The Mitochondrial TOM Complex Is Required for tBid/Bax-induced Cytochrome c Release
The Journal of biological chemistry, 2007Co-Authors: Martin Ott, E Norberg, B Zhivotovsky, Katharina M. Walter, Patrick Schreiner, Christian Kemper, Doron Rapaport, S OrreniusAbstract:Cytochrome c release from mitochondria is a key event in apoptosis signaling that is regulated by Bcl-2 family Proteins. Cleavage of the BH3-only Protein Bid by multiple proteases leads to the formation of truncated Bid (tBid), which, in turn, promotes the oligomerization/insertion of Bax into the mitochondrial outer membrane and the resultant release of Proteins residing in the intermembrane space. Bax, a monomeric Protein in the cytosol, is targeted by a yet unknown mechanism to the mitochondria. Several hypotheses have been put forward to explain this targeting specificity. Using mitochondria isolated from different mutants of the yeast Saccharomyces cerevisiae and recombinant Proteins, we have now investigated components of the mitochondrial outer membrane that might be required for tBid/Bax-induced cytochrome c release. Here, we show that the Protein translocase of the outer mitochondrial membrane is required for Bax insertion and cytochrome c release.
Francesca M. Marassi - One of the best experts on this subject based on the ideXlab platform.
-
Mapping the interaction of pro-apoptotic tBid with pro-survival BCL-XL
Biochemistry, 2009Co-Authors: Yong Yao, Andrey A. Bobkov, Leigh A. Plesniak, Francesca M. MarassiAbstract:The BH3-only BCL-2 family Protein Bid is activated by caspase-8 cleavage upon engagement of cell surface death receptors. The resulting 15 kDa C-terminal fragment, tBid, translocates to mitochondri...
-
mapping the specific cytoprotective interaction of humanin with the pro apoptotic Protein Bid
Chemical Biology & Drug Design, 2007Co-Authors: Jungyuen Choi, Dayong Zhai, Xin Zhou, Arnold C. Satterthwait, John C. Reed, Francesca M. MarassiAbstract:Humanin is a short endogenous peptide, which can provide protection from cell death through its association with various receptors, including the pro-apoptotic Bcl-2 family Proteins Bid, Bim, and Bax. By using NMR chemical shift mapping experiments, we demonstrate that the interaction between Humanin-derived peptides and Bid is specific, and we localize the binding site to a region on the surface of Bid, which includes residues from the conserved helical BH3 domain of the Protein. The BH3 domain mediates the association of Bid with other Bcl-2 family members and is essential for the Protein's cytotoxic activity. The data suggest that Humanin exerts its cytoprotective activity by engaging the Bid BH3 domain; this would hinder the association of Bid with other Bcl-2 family Proteins, thereby mitigating its toxicity. The identification of a Humanin-specific binding site on the surface of Bid reinforces its importance as a direct modulator of programmed cell death, and suggests a strategy for the design of cytoprotective peptide inhibitors of Bid.
-
Mapping the Specific Cytoprotective Interaction of Humanin with the Pro‐apoptotic Protein Bid
Chemical biology & drug design, 2007Co-Authors: Jungyuen Choi, Dayong Zhai, Xin Zhou, Arnold C. Satterthwait, John C. Reed, Francesca M. MarassiAbstract:Humanin is a short endogenous peptide, which can provide protection from cell death through its association with various receptors, including the pro-apoptotic Bcl-2 family Proteins Bid, Bim, and Bax. By using NMR chemical shift mapping experiments, we demonstrate that the interaction between Humanin-derived peptides and Bid is specific, and we localize the binding site to a region on the surface of Bid, which includes residues from the conserved helical BH3 domain of the Protein. The BH3 domain mediates the association of Bid with other Bcl-2 family members and is essential for the Protein's cytotoxic activity. The data suggest that Humanin exerts its cytoprotective activity by engaging the Bid BH3 domain; this would hinder the association of Bid with other Bcl-2 family Proteins, thereby mitigating its toxicity. The identification of a Humanin-specific binding site on the surface of Bid reinforces its importance as a direct modulator of programmed cell death, and suggests a strategy for the design of cytoprotective peptide inhibitors of Bid.
Andreas Strasser - One of the best experts on this subject based on the ideXlab platform.
-
BH3-only Protein Bid is dispensable for seizure-induced neuronal death and the associated nuclear accumulation of apoptosis-inducing factor.
Journal of neurochemistry, 2010Co-Authors: Tobias Engel, Andreas Strasser, Jochen H. M. Prehn, Aurelien Caballero-caballero, Clara K. Schindler, Nikolaus Plesnila, David C. HenshallAbstract:Prolonged seizures activate members of the Bcl-2 homology domain 3-only sub-group of the Bcl-2 Protein family, which are essential for initiation of apoptosis signaling. Bid is a potent pro-apoptotic Bcl-2 homology domain 3-only Protein, which upon proteolytic activation translocates to mitochondria to promote activation of the Bax/Bak sub-group of the pro-apoptotic Bcl-2 family and thereby contributes to release of apoptogenic molecules, such as cytochrome c and possibly apoptosis-inducing factor (AIF). Bid-deficient mice have been reported to show reduced lesion volumes after ischemia and trauma in vivo but a causal role for Bid in the setting of seizure-induced neuronal death has not been investigated. In this study, we studied Bid activation following status epilepticus in mice and compared hippocampal damage between wild-type and Bid-deficient animals. Full-length Bid was detected in normal mouse hippocampus and the cleaved (activated) p15 fragment of Bid was detected shortly after status epilepticus. Bid-deficient mice underwent equivalent electrographic seizure responses during status epilepticus as wild-type animals. Hippocampal counts of degenerating neurons and surviving neuron-specific nuclear Protein-positive cells were not significantly different between wild-type and Bid-deficient mice. Additionally, nuclear translocation of AIF was not reduced in Bid-deficient compared with wild-type animals subjected to status epilepticus. The present study demonstrates that AIF is not dependent on Bid for mitochondrial release and nuclear import in this model and that while Bid is cleaved during seizure-induced neuronal death, it may be functionally redundant or even not essential.
-
Proapoptotic BH3-only Protein Bid is essential for death receptor-induced apoptosis of pancreatic beta-cells.
Diabetes, 2008Co-Authors: Mark D Mckenzie, Thomas Kaufmann, Andreas Strasser, Janette Allison, Emma M. Carrington, David C.s. Huang, Thomas W.h. Kay, Helen E. ThomasAbstract:OBJECTIVE— Apoptosis of pancreatic β-cells is critical in both diabetes development and failure of islet transplantation. The role in these processes of pro- and antiapoptotic Bcl-2 family Proteins, which regulate apoptosis by controlling mitochondrial integrity, remains poorly understood. We investigated the role of the BH3-only Protein Bid and the multi-BH domain proapoptotic Bax and Bak, as well as prosurvival Bcl-2, in β-cell apoptosis. RESEARCH DESIGN AND METHODS— We isolated islets from mice lacking Bid, Bax, or Bak and those overexpressing Bcl-2 and exposed them to Fas ligand, tumor necrosis factor (TNF)-α, and proinflammatory cytokines or cytotoxic stimuli that activate the mitochondrial apoptotic pathway (staurosporine, etoposide, γ-radiation, tunicamycin, and thapsigargin). Nuclear fragmentation was measured by flow cytometry. RESULTS— Development and function of islets were not affected by loss of Bid, and Bid-deficient islets were as susceptible as wild-type islets to cytotoxic stimuli that cause apoptosis via the mitochondrial pathway. In contrast, Bid-deficient islets and those overexpressing antiapoptotic Bcl-2 were protected from Fas ligand–induced apoptosis. Bid-deficient islets were also resistant to apoptosis induced by TNF-α plus cycloheximide and were partially resistant to proinflammatory cytokine-induced death. Loss of the multi-BH domain proapoptotic Bax or Bak protected islets partially from death receptor–induced apoptosis. CONCLUSIONS— These results demonstrate that Bid is essential for death receptor–induced apoptosis of islets, similar to its demonstrated role in hepatocytes. This indicates that blocking Bid activity may be useful for protection of islets from immune-mediated attack and possibly also in other pathological states in which β-cells are destroyed.
-
The BH3-Only Protein Bid Is Dispensable for DNA Damage- and Replicative Stress-Induced Apoptosis or Cell-Cycle Arrest
Cell, 2007Co-Authors: Thomas Kaufmann, Vishva M. Dixit, David C.s. Huang, Lin Tai, Paul G Ekert, Fiona Norris, Ralph K. Lindemann, Ricky W. Johnstone, Andreas StrasserAbstract:Bid, a caspase-activated proapoptotic BH3-only Protein, is essential for Fas-induced hepatocyte destruction. Recent studies published in Cell produced conflicting results, indicating that loss of Bid either protects or enhances apoptosis induced by DNA damage or replicative stress. To resolve this controversy, we generated novel Bid-deficient mice on an inbred C57BL/6 background and removed the drug-selection cassette from the targeted locus. Nine distinct cell types from these Bid-deficient mice underwent cell-cycle arrest and apoptosis in a manner indistinguishable from control WT cells in response to DNA damage or replicative stress. Moreover, we found that even cells from the original Bid-deficient mice responded normally to these stimuli, indicating that differences in genetic background or the presence of a strong promoter within the targeted locus are unlikely to explain the differences between our results and those reported previously. We conclude that Bid has no role in DNA damage- or replicative stress-induced apoptosis or cell-cycle arrest.
-
Response: Does Bid play a role in the DNA damage response?
Cell, 2007Co-Authors: Thomas Kaufmann, Vishva M. Dixit, David C.s. Huang, Lin Tai, Paul G Ekert, Fiona Norris, Ralph K. Lindemann, Ricky W. Johnstone, Damien Arnoult, Andreas StrasserAbstract:We have recently reported (Kaufmann et al., 2007) that, in contrast to two previous publications (Kamer et al., 2005; Zinkel et al., 2005), the proapoptotic BH3-only Protein Bid plays no role in DNA damage-induced or replicative stress-induced cell-cycle arrest or apoptosis. Here we respond to the concerns about our study (Kaufmann et al., 2007) raised by Zinkel et al. in their Correspondence.
-
Loss of the BH3-only Protein Bid does not rescue RelA-deficient embryos from TNF-R1-mediated fatal hepatocyte destruction
Cell death and differentiation, 2006Co-Authors: Thomas Kaufmann, Raffi Gugasyan, Steve Gerondakis, Vishva M. Dixit, Andreas StrasserAbstract:Loss of the BH3-only Protein Bid does not rescue RelA-deficient embryos from TNF-R1-mediated fatal hepatocyte destruction
Nicholas R Lemoine - One of the best experts on this subject based on the ideXlab platform.
-
identification of novel isoforms of the bh3 domain Protein bim which directly activate bax to trigger apoptosis
Molecular and Cellular Biology, 2002Co-Authors: Michela Marani, Tencho Tenev, Julian Downward, David C Hancock, Nicholas R LemoineAbstract:Bim (Bcl-2-interacting mediator of cell death) is a member of the BH3 domain-only subgroup of Bcl-2 family members, for which three splice variants have been described. Bim is expressed in many healthy cell types, where it is maintained in an inactive conformation through binding to the microtubule-associated dynein motor complex. Upon certain apoptotic stimuli, Bim is released from microtubules and mediates caspase-dependent apoptosis through a mechanism that is still unclear. Here, we have identified and characterized novel splice variants of human Bim mRNA. In particular, we show that a newly discovered, small Protein isoform, BimAD, is also able to induce apoptosis strongly in several human cell lines. BimAD and the previously characterized isoform BimS are shown to be capable of heterodimerizing in vivo with both death antagonists (Bcl-2 and Bcl-XL) and death agonists (Bax). Mutants of BimAD that bind to Bax but not to Bcl-2 still promote apoptosis, indicating that Bim can regulate apoptosis through direct activation of the Bax-mediated cell death pathway without interaction with antiapoptotic Bcl-2 family members. Furthermore, we have shown that the interaction of the BimS and BimAD isoforms with Bax leads to a conformational change in this Protein analogous to that triggered by the BH3-only Protein Bid.
