A Bim-activating mould

Häcker, Georg

doi:10.1038/cdd.2013.98

Cited by 3 publications

(5 citation statements)

References 15 publications

(16 reference statements)

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“…RNA sequencing data also demonstrated that gliotoxin induced the expression of genes involved in apoptotic pathways, including BAX and BAK1 . These are relevant findings, as gliotoxin from Aspergillus has been suggested to induce BIM/BAK -dependent apoptosis through JNK-dependent phosphorylation ( 19 ). One potential explanation for not observing a robust activation of genes that mediate cell death in the RNA sequencing experiment could be that cells were only exposed for 1 h, whereas the majority cell death was observed after gliotoxin exposures of 5 h.…”

Section: Discussionmentioning

confidence: 83%

Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells

Abreu

Hampton

Hoffman

et al. 2020

American Journal of Physiology-Lung Cellular and Molecular Phys

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Growing evidence demonstrates that human mesenchymal stromal cells (MSCs) modify their in vivo anti-inflammatory actions depending on the specific inflammatory environment encountered. Understanding this better is crucial to refine MSC-based cell therapies for lung and other diseases. Using acute exacerbations of cystic fibrosis (CF) lung disease as a model, the effects of ex vivo MSC exposure to clinical bronchoalveolar lavage fluid (BALF) samples, as a surrogate for the in vivo clinical lung environment, on MSC viability, gene expression, secreted cytokines, and mitochondrial function was compared to effects of BALF collected from healthy volunteers. CF BALF samples which cultured positive for Aspergillus sp. (Asp) induced rapid MSC death, usually within several hours of exposure. Further analyses suggested the fungal toxin gliotoxin as a potential mediator contributing to CF BALF-induced MSC death. RNA sequencing analyses of MSCs exposed to either Asp+ or Asp- CF BALF samples identified a number of differentially expressed transcripts, including those involved in interferon-signaling, anti-microbial gene expression, and cell death. Toxicity did not correlate with bacterial lung infections. These results suggest that the potential use of MSC-based cell therapies for CF or other lung diseases may not be warranted in the presence of Aspergillus.

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Section: Discussionmentioning

confidence: 83%

Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells

Abreu

Hampton

Hoffman

et al. 2020

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Notably, triplemutated Bim is unable to transduce the gliotoxin-JNK-initiated apoptotic stimulus to Bak. Compared to wild type, mice lacking Bak were significantly less susceptible to A. fumigatus infection, which demonstrates the in vivo relevance of this gliotoxin-induced apoptotic pathway [16,62,75]. In resting cells, NF-kB is localized to the cytoplasm because of binding to inhibitory protein IkB.…”

Section: Discussionmentioning

confidence: 95%

“…Thus, not only has this work elucidated the mechanism of gliotoxin-induced apoptosis but also it has uncovered the molecular mechanisms of Bcl-2 family initiation [16,75]. It is possible that induction of gliotoxindependent apoptosis could impact on the severity and course of Aspergillus infection by destroying lung epithelium or by killing alveolar macrophages [62].…”

Section: Gliotoxin Impact On Animal Cellsmentioning

confidence: 99%

“…In addition to studying how gliotoxin contributes to organismal virulence, it has also been deployed to explore and reveal novel biochemistry within both fungal and animal cells [15,16]. Thus, we contend that it is the ability of gliotoxin to interfere with so many cellular processes that makes it such a useful tool to access the many important, although occluded, systems interactions within fungi.…”

Section: Contextualizing and Rethinking Gliotoxinmentioning

confidence: 99%

“…Amongst others, these include sirodesmin A, sporidesmin A, chaetocin, aranotin, and chetomin [13]. Studies on the biosynthetic mechanism of ETPs, particularly gliotoxin, are also serving to inspire new synthetic chemistry approaches for ETP synthesis and desulfurization, which are somewhat beyond the scope of the present review [13,14].In addition to studying how gliotoxin contributes to organismal virulence, it has also been deployed to explore and reveal novel biochemistry within both fungal and animal cells [15,16]. Thus, we contend that it is the ability of gliotoxin to interfere with so many cellular processes that makes it such a useful tool to access the many important, although occluded, systems interactions within fungi.…”

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confidence: 99%

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Resistance is not futile: gliotoxin biosynthesis, functionality and utility

Dolan¹,

O’Keeffe²,

Jones

et al. 2015

Trends in Microbiology

146

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Gliotoxin biosynthesis is encoded by the gli gene cluster in Aspergillus fumigatus. The biosynthesis of gliotoxin is influenced by a suite of transcriptionally-active regulatory proteins and a bis-thiomethyltransferase. A selfprotection system against gliotoxin is present in A. fumigatus. Several additional metabolites are also produced via the gliotoxin biosynthetic pathway. Moreover, the biosynthesis of unrelated natural products appears to be influenced either by gliotoxin or by the activity of specific reactions within the biosynthetic pathway. The activity of gliotoxin against animal cells and fungi, often mediated by interference with redox homeostasis or protein modification, is revealing new metabolic interactions within eukaryotic systems. Nature has provided a most useful natural product with which to reveal some of its many molecular secrets. Contextualizing and rethinking gliotoxinAspergillus fumigatus is an opportunistic fungal pathogen and primarily infects immunocompromised individuals where it can cause fatal invasive aspergillosis (IA) [1]. A. fumigatus exposure can also induce debilitating aspergillosis and allergy in immunocompetent individuals [2,3]. Selected secondary metabolites produced by A. fumigatus, in particular siderophores and the non-ribosomal peptide gliotoxin, are generally considered to be front-line virulence factors [4,5]. Gliotoxin is an epipolythiodioxopiperazine (ETP) of molecular mass 326 Da, and contains a disulfide bridge which can undergo repeating cleavage and reformation, thereby resulting in a potent intracellular redox activity (Figure 1) [6]. Indeed, the dithiol form of gliotoxin has also been posited to be responsible for the observed biological activities of gliotoxin [7]. Bisdethiobis(methylthio)gliotoxin (BmGT) and related gliotoxin metabolites (Figure 1) are also biosynthesized by A. fumigatus [8,9]. Incredibly, the gliotoxin biosynthetic pathway had remained elusive since the discovery of gliotoxin in 1936; however, recent studies have not only dissected this unusual molecular assembly system but have revealed the necessity for gliotoxin-producing fungi to possess an endogenous resistance system against gliotoxin [10,11]. Moreover, because gliotoxin can be considered as the prototype ETP, studies on gliotoxin can be instrumental in revealing the biosynthetic mechanisms of related ETPs which are biosynthesized by a range of fungi [12]. Amongst others, these include sirodesmin A, sporidesmin A, chaetocin, aranotin, and chetomin [13]. Studies on the biosynthetic mechanism of ETPs, particularly gliotoxin, are also serving to inspire new synthetic chemistry approaches for ETP synthesis and desulfurization, which are somewhat beyond the scope of the present review [13,14].In addition to studying how gliotoxin contributes to organismal virulence, it has also been deployed to explore and reveal novel biochemistry within both fungal and animal cells [15,16]. Thus, we contend that it is the ability of gliotoxin to interfere with so many cellular processes that makes it...

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The apoptotic pore on mitochondria: are we breaking through or still stuck?

Borner

Andrews

2014

Cell Death Differ

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The past 25 years of research has brought us close to understanding the apoptotic form of programmed cell death, a major regulatory mechanism that shapes us during embryogenesis and keeps us properly functional and healthy on a daily basis. We know that mistakes in regulating this process contribute to various human diseases ranging from cancer, autoimmunity, immunodeficiency to neurodegenerative diseases, and we now have novel drugs targeting apoptosisregulatory molecules in development or at hand. Some of these compounds have entered clinical trials and might be beneficial in curing diseases such as cancer, particularly in combination with other classical therapeutics.Apoptosis proceeds through two major signaling pathways, an extrinsic pathway initiated by TNF-like death ligands and an intrinsic pathway involving mitochondrial outer membrane permeabilization (MOMP) triggered by a variety of apoptotic stimuli, such as chemotherapeutic drugs, irradiation, the deprivation of growth factors/cytokines or cell-matrix interactions and others. The molecular mechanisms involved in extrinsic apoptosis signaling induced by TNFa and its related cousin FasL have been largely defined, and basically involve the clustering of their respective receptors and the recruitment and activation of initiator caspases-8 and 10 via the FADD adapter molecule and the subsequent cleavage and activation of the effector caspases-3 and 7 by the initiator caspases. It is also well known that in some particular cells, the extrinsic pathway can crosstalk with the intrinsic pathway via cleavage of the BH3 protein Bid by caspase-8. What might be a deviation of the theme is the signaling pathway induced by the TNF-like ligand TRAIL. In this case, yet unidentified molecules may modulate the caspase-8/caspase-3 activation axis. Moreover, caspase-8 has recently become implicated in novel death signaling pathways that emerge from within the cell such as after viral infection, glucose deprivation or the induction of autophagy. Finally, we know now that under caspase-inhibiting conditions, TNFa can also activate alternative death signaling such as necroptosis, which involves RIP-like protein kinases that may crosstalk with mitochondria.Intrinsic, mitochondria-mediated apoptosis signaling is tightly regulated by members of the Bcl-2 family. A subgroup of the family, the BH3 proteins both 'sense' the apoptotic stimuli by posttranscriptional mechanisms and function as the mediators of transcriptional responses. The full scope of the posttranscriptional mechanisms has not yet been unveiled, but we know that it often exposes and/or structures a particular domain in these proteins, called the BH3 domain, which then is able to activate MOMP via two basic strategies: (i) to bind to the hydrophobic pocket of Bcl-2-like survival factors, such as Bcl-2, Bcl-x L , Bcl-w, Mcl-1 and A1, inhibiting them and thereby releasing the pre-bound third subclass of the family, the Bax and Bak effectors, or (ii) to directly activate Bax and Bak on the mitochondrial membrane. Th...

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A Bim-activating mould

Cited by 3 publications

References 15 publications

Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells

Differential effects of the cystic fibrosis lung inflammatory environment on mesenchymal stromal cells

Resistance is not futile: gliotoxin biosynthesis, functionality and utility

The apoptotic pore on mitochondria: are we breaking through or still stuck?

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