scholarly journals Pleiotropic molecular effects of the Mycobacterium ulcerans virulence factor mycolactone underlying the cell death and immunosuppression seen in Buruli ulcer

2014 ◽  
Vol 42 (1) ◽  
pp. 177-183 ◽  
Author(s):  
Belinda Hall ◽  
Rachel Simmonds
Keyword(s):  
Cell Death ◽  
Virulence Factor ◽  
Cell Biology ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Prolonged Exposure ◽  
Buruli Ulcer ◽  
Eukaryotic Cell ◽  
Cellular Systems ◽  
Mycobacterium Ulcerans

Mycolactone is a polyketide macrolide lipid-like secondary metabolite synthesized by Mycobacterium ulcerans, the causative agent of BU (Buruli ulcer), and is the only virulence factor for this pathogen identified to date. Prolonged exposure to high concentrations of mycolactone is cytotoxic to diverse mammalian cells (albeit with varying efficiency), whereas at lower doses it has a spectrum of immunosuppressive activities. Combined, these pleiotropic properties have a powerful influence on local and systemic cellular function that should explain the pathophysiology of BU disease. The last decade has seen significant advances in our understanding of the molecular mechanisms underlying these effects in a range of different cell types. The present review focuses on the current state of our knowledge of mycolactone function, and its molecular and cellular targets, and seeks to identify commonalities between the different functional and cellular systems. Since mycolactone influences fundamental cellular processes (cell division, cell death and inflammation), getting to the root of how mycolactone achieves this could have a profound impact on our understanding of eukaryotic cell biology.

scholarly journals Fibrillar α-synuclein induces neurotoxic astrocyte activation via RIP kinase signaling and NF-κB

2021 ◽  
Vol 12 (8) ◽  
Author(s):  
Tsui-Wen Chou ◽  
Nydia P. Chang ◽  
Medha Krishnagiri ◽  
Aisha P. Patel ◽  
Marissa Lindman ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Biology ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Neuronal Cell ◽  
Dopamine Neurons ◽  
Functional Markers ◽  
Kinase Signaling ◽  
Astrocyte Activation ◽  
Transcriptional Responses

AbstractParkinson’s disease (PD) is a neurodegenerative disorder characterized by the death of midbrain dopamine neurons. The pathogenesis of PD is poorly understood, though misfolded and/or aggregated forms of the protein α-synuclein have been implicated in several neurodegenerative disease processes, including neuroinflammation and astrocyte activation. Astrocytes in the midbrain play complex roles during PD, initiating both harmful and protective processes that vary over the course of the disease. However, despite their significant regulatory roles during neurodegeneration, the cellular and molecular mechanisms that promote pathogenic astrocyte activity remain mysterious. Here, we show that α-synuclein preformed fibrils (PFFs) induce pathogenic activation of human midbrain astrocytes, marked by inflammatory transcriptional responses, downregulation of phagocytic function, and conferral of neurotoxic activity. These effects required the necroptotic kinases RIPK1 and RIPK3, but were independent of MLKL and necroptosis. Instead, both transcriptional and functional markers of astrocyte activation occurred via RIPK-dependent activation of NF-κB signaling. Our study identifies a previously unknown function for α-synuclein in promoting neurotoxic astrocyte activation, as well as new cell death-independent roles for RIP kinase signaling in the regulation of glial cell biology and neuroinflammation. Together, these findings highlight previously unappreciated molecular mechanisms of pathologic astrocyte activation and neuronal cell death with implications for Parkinsonian neurodegeneration.

scholarly journals Molecular Mechanisms Underpinning the Circulation and Cellular Uptake of Mycobacterium ulcerans Toxin Mycolactone

2021 ◽  
Vol 12 ◽  
Author(s):  
Bruno Tello Rubio ◽  
Florence Bugault ◽  
Blandine Baudon ◽  
Bertrand Raynal ◽  
Sébastien Brûlé ◽  
...  
Keyword(s):  
Cellular Uptake ◽  
Molecular Mechanisms ◽  
Scavenger Receptor ◽  
Buruli Ulcer ◽  
Systemic Circulation ◽  
Mycobacterium Ulcerans ◽  
Host Cells ◽  
Ulcer Disease ◽  
Major Mechanism ◽  
Specific Association

Mycolactone is a diffusible lipid toxin produced by Mycobacterium ulcerans, the causative agent of Buruli ulcer disease. Altough bacterially derived mycolactone has been shown to traffic from cutaneous foci of infection to the bloodstream, the mechanisms underpinning its access to systemic circulation and import by host cells remain largely unknown. Using biophysical and cell-based approaches, we demonstrate that mycolactone specific association to serum albumin and lipoproteins is necessary for its solubilization and is a major mechanism to regulate its bioavailability. We also demonstrate that Scavenger Receptor (SR)-B1 contributes to the cellular uptake of mycolactone. Overall, we suggest a new mechanism of transport and cell entry, challenging the dogma that the toxin enters host cells via passive diffusion.

scholarly journals Molecular mechanisms creating bistable switches at cell cycle transitions

Open Biology ◽  
2013 ◽  
Vol 3 (3) ◽  
pp. 120179 ◽  
Author(s):  
Anael Verdugo ◽  
P. K. Vinod ◽  
John J. Tyson ◽  
Bela Novak
Keyword(s):  
Cell Cycle ◽  
Mammalian Cells ◽  
Feedback Loop ◽  
Molecular Mechanisms ◽  
Eukaryotic Cell ◽  
Mitotic Checkpoint ◽  
Toggle Switch ◽  
Inhibitory Protein ◽  
Common Features ◽  
Cellular Decision Making

Progression through the eukaryotic cell cycle is characterized by specific transitions, where cells move irreversibly from stage i −1 of the cycle into stage i . These irreversible cell cycle transitions are regulated by underlying bistable switches, which share some common features. An inhibitory protein stalls progression, and an activatory protein promotes progression. The inhibitor and activator are locked in a double-negative feedback loop, creating a one-way toggle switch that guarantees an irreversible commitment to move forward through the cell cycle, and it opposes regression from stage i to stage i −1. In many cases, the activator is an enzyme that modifies the inhibitor in multiple steps, whereas the hypo-modified inhibitor binds strongly to the activator and resists its enzymatic activity. These interactions are the basis of a reaction motif that provides a simple and generic account of many characteristic properties of cell cycle transitions. To demonstrate this assertion, we apply the motif in detail to the G1/S transition in budding yeast and to the mitotic checkpoint in mammalian cells. Variations of the motif might support irreversible cellular decision-making in other contexts.

Induction of cell death by radiotherapy.

1999 ◽  
pp. 41-44 ◽  
Author(s):  
G M Ross
Keyword(s):  
Cell Death ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Oxygen Deficiency ◽  
Ionising Radiation ◽  
Cell Cycle Checkpoints ◽  
Physical Damage ◽  
Stress Signals ◽  
Clonogenic Cell ◽  
Spatial Specificity

Ionising radiation remains one of the most effective tools in the therapy of cancer. It combines the properties of an extremely efficient DNA-damaging agent with a high degree of spatial specificity. Nonetheless, there remain considerable differences in the outcome for treatment of tumours of differing histological type treated by radiotherapy. Tumours arising from lymphoid or germ cells are significantly more radiocurable than most solid tumours of epithelial origin. The molecular mechanisms underlying such differences in cellular radiosensitivity are the subject of current research. When normal mammalian cells are subjected to stress signals--e.g. radiation, chemotherapeutic drugs, oxygen deficiency--a range of gene products involved in the sensing and signalling of such stresses are activated. The response of eukaryotic cells to ionising radiation includes activation of DNA repair pathways and cell cycle checkpoints, with subsequent full 'biological' recovery or cell death. Radiation induces two different modes of cell death termed mitotic or clonogenic cell death, and apoptosis. Until recent years, there was surprisingly little mechanistic understanding of the events following induction of physical damage by radiation and biological outcome for the cell. There have been recent major advances in our understanding of the signal transduction pathways involved in determining the fate of cells after irradiation.

scholarly journals The Oxymonad Genome Displays Canonical Eukaryotic Complexity in the Absence of a Mitochondrion

2019 ◽  
Vol 36 (10) ◽  
pp. 2292-2312 ◽  
Author(s):  
Anna Karnkowska ◽  
Sebastian C Treitli ◽  
Ondřej Brzoň ◽  
Lukáš Novák ◽  
Vojtěch Vacek ◽  
...  
Keyword(s):  
Cell Biology ◽  
Acid Metabolism ◽  
Genome Structure ◽  
Eukaryotic Cell ◽  
Cellular Systems ◽  
Cluster Assembly ◽  
Glycine Cleavage System ◽  
Extensive Analysis ◽  
Glycine Cleavage ◽  
And Oxidative Stress

AbstractThe discovery that the protist Monocercomonoides exilis completely lacks mitochondria demonstrates that these organelles are not absolutely essential to eukaryotic cells. However, the degree to which the metabolism and cellular systems of this organism have adapted to the loss of mitochondria is unknown. Here, we report an extensive analysis of the M. exilis genome to address this question. Unexpectedly, we find that M. exilis genome structure and content is similar in complexity to other eukaryotes and less “reduced” than genomes of some other protists from the Metamonada group to which it belongs. Furthermore, the predicted cytoskeletal systems, the organization of endomembrane systems, and biosynthetic pathways also display canonical eukaryotic complexity. The only apparent preadaptation that permitted the loss of mitochondria was the acquisition of the SUF system for Fe–S cluster assembly and the loss of glycine cleavage system. Changes in other systems, including in amino acid metabolism and oxidative stress response, were coincident with the loss of mitochondria but are likely adaptations to the microaerophilic and endobiotic niche rather than the mitochondrial loss per se. Apart from the lack of mitochondria and peroxisomes, we show that M. exilis is a fully elaborated eukaryotic cell that is a promising model system in which eukaryotic cell biology can be investigated in the absence of mitochondria.

scholarly journals A Mycobacterium ulcerans Toxin, Mycolactone, Causes Apoptosis in Guinea Pig Ulcers and Tissue Culture Cells

2000 ◽  
Vol 68 (2) ◽  
pp. 877-883 ◽  
Author(s):  
Kathleen M. George ◽  
Lisa Pascopella ◽  
Diane M. Welty ◽  
P. L. C. Small
Keyword(s):  
Cell Death ◽  
Inflammatory Response ◽  
Guinea Pig ◽  
Tissue Damage ◽  
Buruli Ulcer ◽  
Mouse Fibroblast ◽  
Mycobacterium Ulcerans ◽  
Acute Inflammatory Response ◽  
Pig Skin ◽  
Culture Cells

ABSTRACT Mycobacterium ulcerans is the causative agent of Buruli ulcer, a tropical ulcerative skin disease. One of the most intriguing aspects of this disease is the presence of extensive tissue damage in the absence of an acute inflammatory response. We recently purified and characterized a macrolide toxin, mycolactone, from M. ulcerans. Injection of this molecule into guinea pig skin reproduced cell death and lack of acute inflammatory response similar to that seen following the injection of viable bacteria. We also showed that mycolactone causes a cytopathic effect on mouse fibroblast L929 cells that is characterized by cytoskeletal rearrangements and growth arrest within 48 h. However, these results could not account for the extensive cell death which occurs in Buruli ulcer. The results presented here demonstrate that L929 and J774 mouse macrophage cells die via apoptosis after 3 to 5 days of exposure to mycolactone. Treatment of cells with a pan-caspase inhibitor can inhibit mycolactone-induced apoptosis. We demonstrate that injection of mycolactone into guinea pig skin results in cell death via apoptosis and that the extent of apoptosis increases as the lesion progresses. These results may help to explain why tissue damage in Buruli ulcer is not accompanied by an acute inflammatory response.

scholarly journals Molecular Mechanisms of Fenofibrate-Induced Metabolic Catastrophe and Glioblastoma Cell Death

2014 ◽  
Vol 35 (1) ◽  
pp. 182-198 ◽  
Author(s):  
Anna Wilk ◽  
Dorota Wyczechowska ◽  
Adriana Zapata ◽  
Matthew Dean ◽  
Jennifer Mullinax ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Molecular Mechanisms ◽  
Prolonged Exposure ◽  
Lipid Lowering ◽  
Peroxisome Proliferator ◽  
Glioblastoma Cells ◽  
Tumor Cell Death ◽  
Metabolic Switch

Fenofibrate (FF) is a common lipid-lowering drug and a potent agonist of the peroxisome proliferator-activated receptor alpha (PPARα). FF and several other agonists of PPARα have interesting anticancer properties, and our recent studies demonstrate that FF is very effective against tumor cells of neuroectodermal origin. In spite of these promising anticancer effects, the molecular mechanism(s) of FF-induced tumor cell toxicity remains to be elucidated. Here we report a novel PPARα-independent mechanism explaining FF's cytotoxicityin vitroand in an intracranial mouse model of glioblastoma. The mechanism involves accumulation of FF in the mitochondrial fraction, followed by immediate impairment of mitochondrial respiration at the level of complex I of the electron transport chain. This mitochondrial action sensitizes tested glioblastoma cells to the PPARα-dependent metabolic switch from glycolysis to fatty acid β-oxidation. As a consequence, prolonged exposure to FF depletes intracellular ATP, activates the AMP-activated protein kinase–mammalian target of rapamycin–autophagy pathway, and results in extensive tumor cell death. Interestingly, autophagy activators attenuate and autophagy inhibitors enhance FF-induced glioblastoma cytotoxicity. Our results explain the molecular basis of FF-induced glioblastoma cytotoxicity and reveal a new supplemental therapeutic approach in which intracranial infusion of FF could selectively trigger metabolic catastrophe in glioblastoma cells.

scholarly journals Multiple UBX proteins reduce the ubiquitin threshold of the mammalian p97-UFD1-NPL4 unfoldase

2022 ◽  
Author(s):  
Karim Labib ◽  
Ryo Fujisawa
Keyword(s):  
Cell Biology ◽  
Mammalian Cells ◽  
Coiled Coil ◽  
Eukaryotic Cell ◽  
Ubiquitin Chain ◽  
Ubiquitin Ligase Activity ◽  
Uba Domain ◽  
Quality Control Mechanism ◽  
Ubiquitin Receptors

The unfolding of ubiquitylated proteins by the p97 / Cdc48 ATPase and its ubiquitin receptors Ufd1-Npl4 is essential in many areas of eukaryotic cell biology. Previous studies showed that yeast Cdc48-Ufd1-Npl4 is governed by a quality control mechanism, whereby substrates must be conjugated to at least five ubiquitins. Here we show that substrate processing by mammalian p97-UFD1-NPL4 involves a complex interplay between ubiquitin chain length and additional p97 cofactors. Using disassembly of the ubiquitylated CMG helicase as a model in vitro system, we find that reconstituted p97-UFD1-NPL4 only unfolds substrates with very long ubiquitin chains. However, this high ubiquitin threshold is greatly reduced, to a level resembling yeast Cdc48-Ufd1-Npl4, by the UBXN7, FAF1 or FAF2 partners of mammalian p97-UFD1-NPL4. Stimulation by UBXN7/FAF1/FAF2 requires the UBX domain that connects each factor to p97, together with the ubiquitin-binding UBA domain of UBXN7 and a previously uncharacterised coiled-coil domain in FAF1/FAF2. Furthermore, we show that deletion of the UBXN7 and FAF1 genes impairs CMG disassembly during S-phase and mitosis and sensitises cells to reduced ubiquitin ligase activity. These findings indicate that multiple UBX proteins are important for the efficient unfolding of ubiquitylated proteins by p97-UFD1-NPL4 in mammalian cells.

scholarly journals Identification of Mammalian Sds3 as an Integral Component of the Sin3/Histone Deacetylase Corepressor Complex

2002 ◽  
Vol 22 (8) ◽  
pp. 2743-2750 ◽  
Author(s):  
Leila Alland ◽  
Gregory David ◽  
Hong Shen-Li ◽  
Jason Potes ◽  
Rebecca Muhle ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Cell Biology ◽  
Mammalian Cells ◽  
Chromatin Modification ◽  
Eukaryotic Cell ◽  
Hdac Activity ◽  
Corepressor Complex ◽  
Local Recruitment

ABSTRACT Silencing of gene transcription involves local chromatin modification achieved through the local recruitment of large multiprotein complexes containing histone deacetylase (HDAC) activity. The mammalian corepressors mSin3A and mSin3B have been shown to play a key role in this process by tethering HDACs 1 and 2 to promoter-bound transcription factors. Similar mechanisms appear to be operative in yeast, in which epistasis experiments have established that the mSin3 and HDAC orthologs (SIN3 and RPD3), along with a novel protein, SDS3, function in the same repressor pathway. Here, we report the identification of a component of the mSin3-HDAC complex that bears homology to yeast SDS3, physically associates with mSin3 proteins in vivo, represses transcription in a manner that is partially dependent on HDAC activity, and enables HDAC1 catalytic activity in vivo. That key physical and functional properties are also shared by yeast SDS3 underscores the central role of the Sin3-HDAC-Sds3 complex in eukaryotic cell biology, and the discovery of mSds3 in mammalian cells provides a new avenue for modulating the activity of this complex in human disease.

scholarly journals Mitochondria—hubs for regulating cellular biochemistry: emerging concepts and networks

Open Biology ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 190126 ◽  
Author(s):  
Alexander J. Anderson ◽  
Thomas D. Jackson ◽  
David A. Stroud ◽  
Diana Stojanovski
Keyword(s):  
Cell Death ◽  
Cell Biology ◽  
Energy Production ◽  
Cell Metabolism ◽  
Calcium Signalling ◽  
Cellular Responses ◽  
Eukaryotic Cell ◽  
Cellular Processes ◽  
Key Players ◽  
Cellular Biochemistry

Mitochondria are iconic structures in biochemistry and cell biology, traditionally referred to as the powerhouse of the cell due to a central role in energy production. However, modern-day mitochondria are recognized as key players in eukaryotic cell biology and are known to regulate crucial cellular processes, including calcium signalling, cell metabolism and cell death, to name a few. In this review, we will discuss foundational knowledge in mitochondrial biology and provide snapshots of recent advances that showcase how mitochondrial function regulates other cellular responses.

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