Correction: The Nuclear Receptor NR4A1 Induces a Form of Cell Death Dependent on Autophagy in Mammalian Cells

Background: Zika virus is an emerging arbovirus of global importance. ZIKV infection is associated with a range of neurological complications such as the Congenital Zika Syndrome and Guillain Barré Syndrome. Despite the magnitude of recent outbreaks, there is no specific therapy to prevent or to alleviate disease pathology. Objective: To investigate the role of P-MAPA immunomodulator in Zika-infected THP-1 cells. Methods: THP-1 cells were subjected at Zika virus infection (Multiplicity of Infection = 0.5) followed by treatment with P-MAPA for until 96 hours post-infection. After that, the cell death was analyzed by annexin+/ PI+ and caspase 3/ 7+ staining by flow cytometry. In addition, the virus replication and cell proliferation were accessed by RT-qPCR and Ki67 staining, respectively. Results: We demonstrate that P-MAPA in vitro treatment significantly reduces Zika virus-induced cell death and caspase-3/7 activation on THP-1 infected cells, albeit it has no role in virus replication and cell proliferation. Conclusions: Our study reveals that P-MAPA seems to be a satisfactory alternative to inhibits the effects of Zika virus infection in mammalian cells.

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Identification of types of membrane injuries and cell death using whole cell-based proton-sensitive field-effect transistor systems

The Analyst ◽

10.1039/c7an00502d ◽

2017 ◽

Vol 142 (18) ◽

pp. 3451-3458 ◽

Cited By ~ 5

Author(s):

Yuki Imaizumi ◽

Tatsuro Goda ◽

Akira Matsumoto ◽

Yuji Miyahara

Keyword(s):

Cell Death ◽

Mammalian Cells ◽

Field Effect ◽

Field Effect Transistor ◽

Ph Sensing ◽

Membrane Injury ◽

Whole Cell ◽

Sensing Systems ◽

Effect Transistor ◽

Chemical Stimuli

Membrane injury and apoptosis of mammalian cells by chemical stimuli were distinguished using ammonia-perfused continuous pH-sensing systems.

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ADP-Ribosylation of Actin by the Clostridium botulinum C2 Toxin in Mammalian Cells Results in Delayed Caspase-Dependent Apoptotic Cell Death

Infection and Immunity ◽

10.1128/iai.00651-08 ◽

2008 ◽

Vol 76 (10) ◽

pp. 4600-4608 ◽

Cited By ~ 40

Author(s):

Karin Heine ◽

Sascha Pust ◽

Stefanie Enzenmüller ◽

Holger Barth

Keyword(s):

Cell Death ◽

Cell Lines ◽

Mammalian Cells ◽

Clostridium Botulinum ◽

Apoptotic Cell ◽

Apoptotic Cell Death ◽

Adp Ribosylation ◽

Mammalian Cell Lines ◽

Adp Ribosyltransferase ◽

C2 Toxin

ABSTRACT The binary C2 toxin from Clostridium botulinum mono-ADP-ribosylates G-actin in the cytosol of eukaryotic cells. This modification leads to depolymerization of actin filaments accompanied by cell rounding within 3 h of incubation but does not immediately induce cell death. Here we investigated the long-term responses of mammalian cell lines (HeLa and Vero) following C2 toxin treatment. Cells stayed round even though the toxin was removed from the medium after its internalization into the cells. No unmodified actin reappeared in the C2 toxin-treated cells within 48 h. Despite actin being completely ADP-ribosylated after about 7 h, no obvious decrease in the overall amount of actin was observed for at least 48 h. Therefore, ADP-ribosylation was not a signal for an accelerated degradation of actin in the tested cell lines. C2 toxin treatment resulted in delayed apoptotic cell death that became detectable about 15 to 24 h after toxin application in a portion of the cells. Poly(ADP)-ribosyltransferase 1 (PARP-1) was cleaved in C2 toxin-treated cells, an indication of caspase 3 activation and a hallmark of apoptosis. Furthermore, specific caspase inhibitors prevented C2 toxin-induced apoptosis, implying that caspases 8 and 9 were activated in C2 toxin-treated cells. C2I, the ADP-ribosyltransferase component of the C2 toxin, remained active in the cytosol for at least 48 h, and no extensive degradation of C2I was observed. From our data, we conclude that the long-lived nature of C2I in the host cell cytosol was essential for the nonreversible cytotoxic effect of C2 toxin, resulting in delayed apoptosis of the tested mammalian cells.

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The Long-Lived Nature of Clostridium perfringens Iota Toxin in Mammalian Cells Induces Delayed Apoptosis

Infection and Immunity ◽

10.1128/iai.00710-09 ◽

2009 ◽

Vol 77 (12) ◽

pp. 5593-5601 ◽

Cited By ~ 23

Author(s):

Hanna Hilger ◽

Sascha Pust ◽

Guido von Figura ◽

Eva Kaiser ◽

Bradley G. Stiles ◽

...

Keyword(s):

Cell Death ◽

Clostridium Perfringens ◽

Mammalian Cells ◽

Catalytic Domain ◽

Vero Cells ◽

African Green Monkey Kidney ◽

Adp Ribosylation ◽

Clostridium Perfringens Iota Toxin ◽

Adp Ribosyltransferase ◽

C2 Toxin

ABSTRACT Mono-ADP ribosylation of actin by bacterial toxins, such as Clostridium perfringens iota or Clostridium botulinum C2 toxins, results in rapid depolymerization of actin filaments and cell rounding. Here we report that treatment of African green monkey kidney (Vero) cells with iota toxin resulted in delayed caspase-dependent death. Unmodified actin did not reappear in toxin-treated cells, and enzyme-active toxin was detectable in the cytosol for at least 24 h. C2 toxin showed comparable, long-lived effects in cells, while a C2 toxin control lacking ADP-ribosyltransferase activity did not induce cell death. To address whether the remarkable stability of the iota and C2 toxins in cytosol was crucial for inducing cell death, we treated cells with C/SpvB, the catalytic domain of Salmonella enterica SpvB. Although C/SpvB also mono-ADP ribosylates actin as do the iota and C2 toxins, cells treated with a cell-permeating C/SpvB fusion toxin became rounded but recovered and remained viable. Moreover, unmodified actin reappeared in these cells, and ADP-ribosyltransferase activity due to C/SpvB was not detectable in the cytosol after 24 h, a result most likely due to degradation of C/SpvB. Repeated application of C/SpvB prevented recovery of cells and reappearance of unmodified actin. In conclusion, a complete but transient ADP ribosylation of actin was not sufficient to trigger apoptosis, implying that long-term stability of actin-ADP-ribosylating toxins, such as iota and C2, in the cytosol is crucial for inducing delayed, caspase-dependent cell death.

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T-2 mycotoxin induced apoptosis in broiler’s liver tissue

Papers on Anthropology ◽

10.12697/poa.2018.27.1.01 ◽

2018 ◽

Vol 27 (1) ◽

pp. 9-16

Author(s):

Piret Hussar ◽

Tõnu Järveots ◽

Lazo Pendovski ◽

Katerina Blagoevska ◽

Trpe Ristoski ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Liver Tissue ◽

Immunohistochemical Staining ◽

Mammalian Cells ◽

Gallus Domesticus ◽

Gallus Gallus Domesticus ◽

Histopathological Changes ◽

Induced Apoptosis ◽

Multicellular Organisms

Apoptosis is a process of programmed cell death that occurs in multicellular organisms. As T-2 toxin is known to induce apoptosis in mammalian cells, the aim of the present experiment was to study the toxic effect of T-2 on chicken liver tissue using apoptosis-related antibodies p21 and p53 which are involved in the p53/p21-mediated apoptotic signalling pathway. The experiment was conducted on fourteen 40-day-old broilers (Gallus gallus domesticus) who were divided into control and T-2 toxin groups. For the T-2 toxin group, T-2 toxin (Sigma, Germany) was dissolved in water and given per os for three consecutive days. The material of the liver was taken 24 hours after the last application. The specimens were fixed with 10% formalin and embedded into paraffin; slices 5 μm in thickness were cut followed by immunohistochemical staining with polyclonal primary antibodies p21 and p53 (Abcam, UK) according to the manufacturer’s guidelines (IHC kit, Abcam, UK). Strong expression of p21 and p53 found in hepatocytes, endotheliocytes and around blood vessels together with large tissue destructions in T-2 toxin group birds’ liver indicates apoptosis and histopathological changes in liver tissue during T-2 mycotoxicosis.

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Multiple Parameters Beyond Lipid Binding Affinity Drive Cytotoxicity of Cholesterol-Dependent Cytolysins

Toxins ◽

10.3390/toxins11010001 ◽

2018 ◽

Vol 11 (1) ◽

pp. 1 ◽

Cited By ~ 4

Author(s):

Sucharit Ray ◽

Roshan Thapa ◽

Peter Keyel

Keyword(s):

Cell Death ◽

Binding Affinity ◽

Hemolytic Activity ◽

Mammalian Cells ◽

Pathogenic Bacteria ◽

Calcium Influx ◽

Membrane Binding ◽

Lipid Binding ◽

Membrane Repair ◽

Death Kinetics

The largest superfamily of bacterial virulence factors is pore-forming toxins (PFTs). PFTs are secreted by both pathogenic and non-pathogenic bacteria. PFTs sometimes kill or induce pro-pathogen signaling in mammalian cells, all primarily through plasma membrane perforation, though the parameters that determine these outcomes are unclear. Membrane binding, calcium influx, pore size, and membrane repair are factors that influence PFT cytotoxicity. To test the contribution of membrane binding to cytotoxicity and repair, we compared the closely related, similarly-sized PFTs Perfringolysin O (PFO) from Clostridium perfringens and Streptolysin O (SLO) from Streptococcus pyogenes. Cell death kinetics for PFO and SLO were different because PFO increased in cytotoxicity over time. We introduced known L3 loop mutations that swap binding affinity between toxins and measured hemolytic activity, nucleated cell death kinetics and membrane repair using viability assays, and live cell imaging. Altered hemolytic activity was directly proportional to toxin binding affinity. In contrast, L3 loop alterations reduced nucleated cell death, and they had limited effects on cytotoxicity kinetics and membrane repair. This suggests other toxin structural features, like oligomerization, drives these parameters. Overall, these findings suggest that repair mechanisms and toxin oligomerization add constraints beyond membrane binding on toxin evolution and activity against nucleated cells.

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Unimpaired thymic and peripheral T cell death in mice lacking the nuclear receptor NGFI-B (Nur77)

Science ◽

10.1126/science.7624775 ◽

1995 ◽

Vol 269 (5223) ◽

pp. 532-535 ◽

Cited By ~ 188

Author(s):

S. Lee ◽

R. Wesselschmidt ◽

G. Linette ◽

O Kanagawa ◽

J. Russell ◽

...

Keyword(s):

Cell Death ◽

T Cell ◽

Nuclear Receptor

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Interaction with Sug1 enables Ipaf ubiquitination leading to caspase 8 activation and cell death

Biochemical Journal ◽

10.1042/bj20091349 ◽

2010 ◽

Vol 427 (1) ◽

pp. 91-104 ◽

Cited By ~ 26

Author(s):

Yatender Kumar ◽

Vegesna Radha ◽

Ghanshyam Swarup

Keyword(s):

Cell Death ◽

Mammalian Cells ◽

Intramolecular Interaction ◽

Dominant Negative ◽

26S Proteasome ◽

Caspase 8 ◽

Interacting Protein ◽

Caspase 1 ◽

Lung Carcinoma Cells ◽

Lrr Domain

Activation of initiator caspases is dependent on interacting proteins, and Ipaf [ICE (interleukin-1β-converting enzyme)-protease activating factor] {NLRC4 [NLR (Nod-like receptor) family CARD (caspase activation and recruitment domain)-containing 4]} an inflammasome component, is involved in caspase 1 activation and apoptosis. Investigating the mechanisms of Ipaf activation, we found that the C-terminal LRR (leucine-rich repeat) domain of Ipaf, through intramolecular interaction, negatively regulates its apoptosis-inducing function. In A549 lung carcinoma cells, expression of Ac-Ipaf (LRR-domain-deleted Ipaf) induced cell death that was dependent on caspase 8, but not on caspase 1. A yeast two-hybrid screen using Ac-Ipaf as bait identified human Sug1 (suppressor of gal 1), a component of the 26S proteasome, as an interacting protein. In mammalian cells Sug1 interacts and co-localizes with Ipaf. Sug1 binds to amino acids 91–253 of Ipaf, which is also the region that the LRR domain binds to. It potentiates cell death induced by Ipaf and Ac-Ipaf, and co-expression of Sug1 and Ipaf induces caspase-8-dependent cell death. Cellular complexes formed by Ipaf and Sug1 contain caspase 8. Expression of Ac-Ipaf or co-expression of Sug1 with Ipaf results in the formation of cytoplasmic aggregates and caspase 8 activation. Sug1 co-expression enabled modification of Ipaf by ubiquitination. Tagging ubiquitin molecules to Ipaf led to aggregate formation, enhanced caspase 8 interaction and activation, resulting in induction of cell death. Using RNAi (RNA interference) and dominant-negative approaches, we have shown that cell death induced by Ac-Ipaf expression or by treatment with TNF-α (tumour necrosis factor α) or doxorubicin is dependent on Sug1. Our results suggest a role for ubiquitination of Ipaf that is enabled by its interaction with Sug1, leading to caspase 8 activation and cell death.

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