The Dark Side of Cell Fusion Bastida-Ruiz, Daniel; Van Hoesen, Kylie; Cohen, Marie
International journal of molecular sciences,
05/2016, Letnik:
17, Številka:
5
Journal Article
Recenzirano
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Cell fusion is a physiological cellular process essential for fertilization, viral entry, muscle differentiation and placental development, among others. In this review, we will highlight the ...different cancer cell-cell fusions and the advantages obtained by these fusions. We will specially focus on the acquisition of metastatic features by cancer cells after fusion with bone marrow-derived cells. The mechanism by which cancer cells fuse with other cells has been poorly studied thus far, but the presence in several cancer cells of syncytin, a trophoblastic fusogen, leads us to a cancer cell fusion mechanism similar to the one used by the trophoblasts. The mechanism by which cancer cells perform the cell fusion could be an interesting target for cancer therapy.
Human mitoNEET (mNT) and CISD2 are two NEET proteins characterized by an atypical 2Fe-2S cluster coordination involving three cysteines and one histidine. They act as redox switches with an active ...state linked to the oxidation of their cluster. In the present study, we show that reduced glutathione but also free thiol-containing molecules such as β-mercaptoethanol can induce a loss of the mNT cluster under aerobic conditions, while CISD2 cluster appears more resistant. This disassembly occurs through a radical-based mechanism as previously observed with the bacterial SoxR. Interestingly, adding cysteine prevents glutathione-induced cluster loss. At low pH, glutathione can bind mNT in the vicinity of the cluster. These results suggest a potential new regulation mechanism of mNT activity by glutathione, an essential actor of the intracellular redox state.
Reduced glutathione can induce a degradation of the mitoNEET cluster under aerobic conditions through a radical-based mechanism. At low pH, glutathione can bind to mitoNEET in the vicinity of the cluster. Display omitted
•Free thiol-containing molecules such as reduced glutathione degrades mNT's cluster in vitro.•Degradation through a radical-based mechanism.•GSH binds at the vicinity of the cluster at acidic pH.•Regulation of mNT activity by GSH.
Lipid droplet metabolism and secretory pathway trafficking both require activation of the Arf1 small G protein. The spatiotemporal regulation of Arf1 activation is mediated by guanine nucleotide ...exchange factors (GEFs) of the GBF and BIG families, but the mechanisms of their localization to multiple sites within cells are poorly understood. Here we show that GBF1 has a lipid-binding domain (HDS1) immediately downstream of the catalytic Sec7 domain, which mediates association with both lipid droplets and Golgi membranes in cells, and with bilayer liposomes and artificial droplets in vitro. An amphipathic helix within HDS1 is necessary and sufficient for lipid binding, both in vitro and in cells. The HDS1 domain of GBF1 is stably associated with lipid droplets in cells, and the catalytic Sec7 domain inhibits this potent lipid-droplet-binding capacity. Additional sequences upstream of the Sec7 domain-HDS1 tandem are required for localization to Golgi membranes. This mechanism provides insight into crosstalk between lipid droplet function and secretory trafficking.
Human mitoNEET (mNT) is the first identified Fe-S protein of the mammalian outer mitochondrial membrane. Recently, mNT has been implicated in cytosolic Fe-S repair of a key regulator of cellular iron ...homeostasis. Here, we aimed to decipher the mechanism by which mNT triggers its Fe-S repair capacity. By using tightly controlled reactions combined with complementary spectroscopic approaches, we have determined the differential roles played by both the redox state of the mNT cluster and dioxygen in cluster transfer and protein stability. We unambiguously demonstrated that only the oxidized state of the mNT cluster triggers cluster transfer to a generic acceptor protein and that dioxygen is neither required for the cluster transfer reaction nor does it affect the transfer rate. In the absence of apo-acceptors, a large fraction of the oxidized holo-mNT form is converted back to reduced holo-mNT under low oxygen tension. Reduced holo-mNT, which holds a 2Fe-2S+ with a global protein fold similar to that of the oxidized form is, by contrast, resistant in losing its cluster or in transferring it. Our findings thus demonstrate that mNT uses an iron-based redox switch mechanism to regulate the transfer of its cluster. The oxidized state is the “active state,” which reacts promptly to initiate Fe-S transfer independently of dioxygen, whereas the reduced state is a “dormant form.” Finally, we propose that the redox-sensing function of mNT is a key component of the cellular adaptive response to help stress-sensitive Fe-S proteins recover from oxidative injury.
Improving knowledge about influenza transmission is crucial to upgrade surveillance network and to develop accurate predicting models to enhance public health intervention strategies. Epidemics ...usually occur in winter in temperate countries and during the rainy season for tropical countries, suggesting a climate impact on influenza spread. Despite a lot of studies, the role of weather on influenza spread is not yet fully understood. In the present study, we investigated this issue at two different levels.
First, we evaluated how weekly (intra-annual) incidence variations of clinical diseases could be linked to those of climatic factors. We considered that only a fraction of the human population is susceptible at the beginning of a year due to immunity acquired from previous years. Second, we focused on epidemic sizes (cumulated number of clinical reported cases) and looked at how their inter-annual and regional variations could be related to differences in the winter climatic conditions of the epidemic years over the regions. We quantified the impact of fifteen climatic variables in France using the Réseau des GROG surveillance network incidence data over eleven regions and nine years.
At the epidemic scale, no impact of climatic factors was highlighted. At the intra-annual scale, six climatic variables had a significant impact: average temperature (5.54 ± 1.09 %), absolute humidity (5.94 ± 1.08 %), daily variation of absolute humidity (3.02 ± 1.17 %), sunshine duration (3.46 ± 1.06 %), relative humidity (4.92 ± 1.20 %) and daily variation of relative humidity (4.46 ± 1.24 %). Since in practice the impact of two highly correlated variables is very hard to disentangle, we performed a principal component analysis that revealed two groups of three highly correlated climatic variables: one including the first three highlighted climatic variables on the one hand, the other including the last three ones on the other hand.
These results suggest that, among the six factors that appeared to be significant, only two (one per group) could in fact have a real effect on influenza spread, although it is not possible to determine which one based on a purely statistical argument. Our results support the idea of an important role of climate on the spread of influenza.
The NEET proteins, an important family of iron-sulfur (Fe-S) proteins, have generated a strong interest due to their involvement in diverse diseases such as cancer, diabetes, and neurodegenerative ...disorders. Among the human NEET proteins, CISD3 has been the least studied, and its functional role is still largely unknown. We have investigated the biochemical features of CISD3 at the atomic and in cellulo levels upon challenge with different stress conditions i.e., iron deficiency, exposure to hydrogen peroxide, and nitric oxide. The redox and cellular stability properties of the protein agree on a predominance of reduced form of CISD3 in the cells. Upon the addition of iron chelators, CISD3 loses its Fe-S clusters and becomes unstructured, and its cellular level drastically decreases. Chemical shift perturbation measurements suggest that, upon cluster oxidation, the protein undergoes a conformational change at the C-terminal CDGSH domain, which determines the instability of the oxidized state. This redox-associated conformational change may be the source of cooperative electron transfer via the two Fe2S2 clusters in CISD3, which displays a single sharp voltammetric signal at −31 mV versus SHE. Oxidized CISD3 is particularly sensitive to the presence of hydrogen peroxide in vitro, whereas only the reduced form is able to bind nitric oxide. Paramagnetic NMR provides clear evidence that, upon NO binding, the cluster is disassembled but iron ions are still bound to the protein. Accordingly, in cellulo CISD3 is unaffected by oxidative stress induced by hydrogen peroxide but it becomes highly unstable in response to nitric oxide treatment.
Malaria, caused by protozoan parasites, is a major public health issue in subtropical countries. An arsenal of antimalarial treatments is available, however, resistance is spreading, calling for the ...development of new antimalarial compounds. The new lead antimalarial drug plasmodione is a redox-active compound that impairs the redox balance of parasites leading to cell death. Based on extensive in vitro assays, a model of its mode of action was drawn, involving the generation of active plasmodione metabolites that act as subversive substrates of flavoproteins, initiating a redox cycling process producing reactive oxygen species. We showed that, in yeast, the mitochondrial respiratory chain NADH-dehydrogenases are the main redox-cycling target enzymes. Furthermore, our data supported the proposal that plasmodione is a pro-drug acting via its benzhydrol and benzoyl metabolites. Here, we selected plasmodione-resistant yeast mutants to further decipher plasmodione mode of action. Of the eleven mutants analysed, nine harboured a mutation in the FAD binding subunit of succinate dehydrogenase (SDH). The analysis of the SDH mutations points towards a specific role for SDH-bound FAD in plasmodione bioactivation, possibly in the first step of the process, highlighting a novel property of SDH.
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•Plasmodione is a new antimalarial redox-active and fast-acting lead agent.•The yeast model is used to generate drug resistance and to decipher mode of action.•Plasmodione is a prodrug of subversive substrates of mitochondrial flavoenzymes.•The succinate dehydrogenase-bound FAD is key for plasmodione bioactivation.
The Truth and Reconciliation Commission of Canada made it clear that understanding the historical, social, cultural, and political landscape that shapes the relationships between Indigenous peoples ...and social institutions, including the health care system, is crucial to achieving social justice. How to translate this recognition into more equitable health policy and practice remains a challenge. In particular, there is limited understanding of ways to respond to situations in which conventional practices mandated by the state and regulated by its legal apparatus come into direct conflict with the values and autonomy of Indigenous individuals, communities, and nations. In this paper, we consider two cases of conflict between Indigenous and biomedical perspectives to clarify some of the competing values. We argue for the importance of person‐ and people‐centered approaches to health care. These value conflicts must be understood at multiple levels to clarify their personal, social, cultural, and political dimensions. Taking into account the divergence between epistemic cultures and communities allows us to understand the multiple narratives deployed in decision‐making processes in clinical, community, and juridical contexts. Recognizing the knowledge claims of Indigenous peoples in health care can help clinicians avoid reinforcing the divides created by the structural and institutional legacy of colonialism. This analysis also provides ways to adjudicate conflicts in health care decision‐making by disentangling cultural, political, medical, and pragmatic issues to allow for respectful dialogue. Insofar as the engagement with cultural pluralism in health care rights is conducted with reciprocal recognition, the medical community and Indigenous peoples can address together the difficult question of how to integrate different epistemic cultures in the health care system.
Malaria is caused by protozoan parasites and remains a major public health issue in subtropical areas. Plasmodione (3-4-(trifluoromethyl)benzyl-menadione) is a novel early lead compound displaying ...fast-acting antimalarial activity. Treatment with this redox active compound disrupts the redox balance of parasite-infected red blood cells. In vitro, the benzoyl analogue of plasmodione can act as a subversive substrate of the parasite flavoprotein NADPH-dependent glutathione reductase, initiating a redox cycling process producing ROS. Whether this is also true in vivo remains to be investigated. Here, we used the yeast model to investigate the mode of action of plasmodione and uncover enzymes and pathways involved in its activity. We showed that plasmodione is a potent inhibitor of yeast respiratory growth, that in drug-treated cells, the ROS-sensitive aconitase was impaired and that cells with a lower oxidative stress defence were highly sensitive to the drug, indicating that plasmodione may act via an oxidative stress.
We found that the mitochondrial respiratory chain flavoprotein NADH-dehydrogenases play a key role in plasmodione activity. Plasmodione and metabolites act as substrates of these enzymes, the reaction resulting in ROS production. This in turn would damage ROS-sensitive enzymes leading to growth arrest. Our data further suggest that plasmodione is a pro-drug whose activity is mainly mediated by its benzhydrol and benzoyl metabolites. Our results in yeast are coherent with existing data obtained in vitro and in Plasmodium falciparum, and provide additional hypotheses that should be investigated in parasites.
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•Malaria is a major public health issue.•The mode of action of the antimalarial plasmodione is not fully understood.•In the yeast model, NADH-dehydrogenases play a key role in its activity.•Plasmodione metabolites are efficient substrates of these enzymes.•The reaction results in ROS production, leading to growth arrest.
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