Inhibition of IκBα phosphorylation potentiates regulated cell death induced by azidothymidine in HTLV-1 infected cells

Chinese giant salamander iridovirus (GSIV) is the causative pathogen of Chinese giant salamander (Andrias davidianus) iridovirosis, leading to severe infectious disease and huge economic losses. However, the infection mechanism by GSIV is far from clear. In this study, a Chinese giant salamander muscle (GSM) cell line is used to investigate the mechanism of cell death during GSIV infection. Microscopy observation and DNA ladder analysis revealed that DNA fragmentation happens during GSIV infection. Flow cytometry analysis showed that apoptotic cells in GSIV-infected cells were significantly higher than that in control cells. Caspase 8, 9, and 3 were activated in GSIV-infected cells compared with the uninfected cells. Consistently, mitochondria membrane potential (MMP) was significantly reduced, and cytochrome c was released into cytosol during GSIV infection. p53 expression increased at an early stage of GSIV infection and then slightly decreased late in infection. Furthermore, mRNA expression levels of pro-apoptotic genes participating in the extrinsic and intrinsic pathway were significantly up-regulated during GSIV infection, while those of anti-apoptotic genes were restrained in early infection and then rose in late infection. These results collectively indicate that GSIV induces GSM apoptotic cell death involving mitochondrial damage, caspases activation, p53 expression, and pro-apoptotic molecules up-regulation.

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Cryo-EM structural analysis of FADD:Caspase-8 complexes defines the catalytic dimer architecture for co-ordinated control of cell fate

Nature Communications ◽

10.1038/s41467-020-20806-9 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Joanna L. Fox ◽

Michelle A. Hughes ◽

Xin Meng ◽

Nikola A. Sarnowska ◽

Ian R. Powley ◽

...

Keyword(s):

Cell Death ◽

Structural Analysis ◽

Cell Fate ◽

Catalytic Domain ◽

Caspase 8 ◽

Type I ◽

Signaling Complex ◽

Catalytic Domains ◽

Regulated Cell Death ◽

Death Effector

AbstractRegulated cell death is essential in development and cellular homeostasis. Multi-protein platforms, including the Death-Inducing Signaling Complex (DISC), co-ordinate cell fate via a core FADD:Caspase-8 complex and its regulatory partners, such as the cell death inhibitor c-FLIP. Here, using electron microscopy, we visualize full-length procaspase-8 in complex with FADD. Our structural analysis now reveals how the FADD-nucleated tandem death effector domain (tDED) helical filament is required to orientate the procaspase-8 catalytic domains, enabling their activation via anti-parallel dimerization. Strikingly, recruitment of c-FLIPS into this complex inhibits Caspase-8 activity by altering tDED triple helix architecture, resulting in steric hindrance of the canonical tDED Type I binding site. This prevents both Caspase-8 catalytic domain assembly and tDED helical filament elongation. Our findings reveal how the plasticity, composition and architecture of the core FADD:Caspase-8 complex critically defines life/death decisions not only via the DISC, but across multiple key signaling platforms including TNF complex II, the ripoptosome, and RIPK1/RIPK3 necrosome.

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Lytic regulated cell death in aquaculture fish

Reviews in Aquaculture ◽

10.1111/raq.12533 ◽

2021 ◽

Author(s):

Xiaojing Xia ◽

Bin He ◽

Xiulin Zhang ◽

Zhe Cheng ◽

Mingcheng Liu ◽

...

Keyword(s):

Cell Death ◽

Regulated Cell Death ◽

Aquaculture Fish

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Implication of ferroptosis in aging

Cell Death Discovery ◽

10.1038/s41420-021-00553-6 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Maryam Mazhar ◽

Ahmad Ud Din ◽

Hamid Ali ◽

Guoqiang Yang ◽

Wei Ren ◽

...

Keyword(s):

Cell Death ◽

Neurological Disorders ◽

Accelerated Aging ◽

Underlying Mechanism ◽

Toxic Chemicals ◽

Whole Body ◽

Regulated Cell Death ◽

Age Related ◽

The Subject ◽

Conventional Cell

AbstractLife is indeed continuously going through the irreversible and inevitable process of aging. The rate of aging process depends on various factors and varies individually. These factors include various environmental stimuli including exposure to toxic chemicals, psychological stress whereas suffering with various illnesses specially the chronic diseases serve as endogenous triggers. The basic underlying mechanism for all kinds of stresses is now known to be manifested as production of excessive ROS, exhaustion of ROS neutralizing antioxidant enzymes and proteins leading to imbalance in oxidation and antioxidant processes with subsequent oxidative stress induced inflammation affecting the cells, tissues, organs and the whole body. All these factors lead to conventional cell death either through necrosis, apoptosis, or autophagy. Currently, a newly identified mechanism of iron dependent regulated cell death called ferroptosis, is of special interest for its implication in pathogenesis of various diseases such as cardiovascular disease, neurological disorders, cancers, and various other age-related disorders (ARD). In ferroptosis, the cell death occur neither by conventional apoptosis, necrosis nor by autophagy, rather dysregulated iron in the cell mediates excessive lipid peroxidation of accumulated lethal lipids. It is not surprising to assume its role in aging as previous research have identified some solid cues on the subject. In this review, we will highlight the factual evidences to support the possible role and implication of ferroptosis in aging in order to declare the need to identify and explore the interventions to prevent excessive ferroptosis leading to accelerated aging and associated liabilities of aging.

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Biomarkers of Radiotherapy-Induced Immunogenic Cell Death

Cells ◽

10.3390/cells10040930 ◽

2021 ◽

Vol 10 (4) ◽

pp. 930

Author(s):

Rianne D. W. Vaes ◽

Lizza E. L. Hendriks ◽

Marc Vooijs ◽

Dirk De Ruysscher

Keyword(s):

Cell Death ◽

Immune Responses ◽

Tumor Cells ◽

Immunogenic Cell Death ◽

Type I ◽

Future Studies ◽

Regulated Cell Death ◽

Molecular Patterns ◽

Damage Associated Molecular Patterns ◽

Potential Biomarkers

Radiation therapy (RT) can induce an immunogenic variant of regulated cell death that can initiate clinically relevant tumor-targeting immune responses. Immunogenic cell death (ICD) is accompanied by the exposure and release of damage-associated molecular patterns (DAMPs), chemokine release, and stimulation of type I interferon (IFN-I) responses. In recent years, intensive research has unraveled major mechanistic aspects of RT-induced ICD and has resulted in the identification of immunogenic factors that are released by irradiated tumor cells. However, so far, only a limited number of studies have searched for potential biomarkers that can be used to predict if irradiated tumor cells undergo ICD that can elicit an effective immunogenic anti-tumor response. In this article, we summarize the available literature on potential biomarkers of RT-induced ICD that have been evaluated in cancer patients. Additionally, we discuss the clinical relevance of these findings and important aspects that should be considered in future studies.

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Oxidative stress and regulated cell death in Parkinson’s disease

Ageing Research Reviews ◽

10.1016/j.arr.2021.101263 ◽

2021 ◽

Vol 67 ◽

pp. 101263

Author(s):

P.A. Dionísio ◽

J.D. Amaral ◽

C.M.P. Rodrigues

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Cell Death ◽

Regulated Cell Death

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Lipid peroxidation and the subsequent cell death transmitting from ferroptotic cells to neighboring cells

Cell Death and Disease ◽

10.1038/s41419-021-03613-y ◽

2021 ◽

Vol 12 (4) ◽

Author(s):

Hironari Nishizawa ◽

Mitsuyo Matsumoto ◽

Guan Chen ◽

Yusho Ishii ◽

Keisuke Tada ◽

...

Keyword(s):

Lipid Peroxidation ◽

Cell Death ◽

Lipid Peroxide ◽

Nih3t3 Cells ◽

Regulated Cell Death ◽

Primary Mouse ◽

Ischemic Diseases ◽

A Chain ◽

Dying Cells

AbstractFerroptosis is a regulated cell death due to the iron-dependent accumulation of lipid peroxide. Ferroptosis is known to constitute the pathology of ischemic diseases, neurodegenerative diseases, and steatohepatitis and also works as a suppressing mechanism against cancer. However, how ferroptotic cells affect surrounding cells remains elusive. We herein report the transfer phenomenon of lipid peroxidation and cell death from ferroptotic cells to nearby cells that are not exposed to ferroptotic inducers (FINs). While primary mouse embryonic fibroblasts (MEFs) and NIH3T3 cells contained senescence-associated β-galactosidase (SA-β-gal)-positive cells, they were decreased upon induction of ferroptosis with FINs. The SA-β-gal decrease was inhibited by ferroptotic inhibitors and knockdown of Atg7, pointing to the involvement of lipid peroxidation and activated autophagosome formation during ferroptosis. A transfer of cell culture medium of cells treated with FINs, type 1 or 2, caused the reduction in SA-β-gal-positive cells in recipient cells that had not been exposed to FINs. Real-time imaging of Kusabira Orange-marked reporter MEFs cocultured with ferroptotic cells showed the generation of lipid peroxide and deaths of the reporter cells. These results indicate that lipid peroxidation and its aftereffects propagate from ferroptotic cells to surrounding cells, even when the surrounding cells are not exposed to FINs. Ferroptotic cells are not merely dying cells but also work as signal transmitters inducing a chain of further ferroptosis.

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Reduced sphingosine kinase 1 activity in dengue virus type-2 infected cells can be mediated by the 3′ untranslated region of dengue virus type-2 RNA

Journal of General Virology ◽

10.1099/vir.0.055616-0 ◽

2013 ◽

Vol 94 (11) ◽

pp. 2437-2448 ◽

Cited By ~ 19

Author(s):

J. M. Carr ◽

T. Kua ◽

J. N. Clarke ◽

J. K Calvert ◽

J. R. Zebol ◽

...

Keyword(s):

Cell Death ◽

Dengue Virus ◽

Virus Type ◽

Elongation Factor ◽

Sphingosine Kinase ◽

Sphingosine Kinase 1 ◽

Diarrhea Virus ◽

Infected Cells ◽

Dengue Virus Type 2

Sphingosine kinase 1 (SphK1) is a lipid kinase with important roles including regulation of cell survival. We have previously shown reduced SphK1 activity in cells with an established dengue virus type-2 (DENV-2) infection. In this study, we examined the effect of alterations in SphK1 activity on DENV-2 replication and cell death and determined the mechanisms of the reduction in SphK1 activity. Chemical inhibition or overexpression of SphK1 after established DENV-2 infection had no effect on infectious DENV-2 production, although inhibition of SphK1 resulted in enhanced DENV-2-induced cell death. Reduced SphK1 activity was observed in multiple cell types, regardless of the ability of DENV-2 infection to be cytopathic, and was mediated by a post-translational mechanism. Unlike bovine viral diarrhea virus, where SphK1 activity is decreased by the NS3 protein, SphK1 activity was not affected by DENV-2 NS3 but, instead, was reduced by expression of the terminal 396 bases of the 3′ UTR of DENV-2 RNA. We have previously shown that eukaryotic elongation factor 1A (eEF1A) is a direct activator of SphK1 and here DENV-2 RNA co-localized and co-precipitated with eEF1A from infected cells. We propose that the reduction in SphK1 activity late in DENV-2-infected cells is a consequence of DENV-2 out-competing SphK1 for eEF1A binding and hijacking cellular eEF1A for its own replication strategy, rather than a specific host or virus-induced change in SphK1 to modulate viral replication. Nonetheless, reduced SphK1 activity may have important consequences for survival or death of the infected cell.

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Ion channels in regulated cell death

Cellular and Molecular Life Sciences ◽

10.1007/s00018-016-2208-z ◽

2016 ◽

Vol 73 (11-12) ◽

pp. 2387-2403 ◽

Cited By ~ 46

Author(s):

Karl Kunzelmann

Keyword(s):

Cell Death ◽

Ion Channels ◽

Regulated Cell Death

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AnIn VivoZebrafish Model for Interrogating ROS-Mediated Pancreaticβ-Cell Injury, Response, and Prevention

Oxidative Medicine and Cellular Longevity ◽

10.1155/2018/1324739 ◽

2018 ◽

Vol 2018 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

Abhishek A. Kulkarni ◽

Abass M. Conteh ◽

Cody A. Sorrell ◽

Anjali Mirmira ◽

Sarah A. Tersey ◽

...

Keyword(s):

Cell Death ◽

Caspase 3 ◽

Cell Injury ◽

Zebrafish Model ◽

Chemical Genetic ◽

Regulated Cell Death ◽

Specific Manner ◽

High Doses

It is well known that a chronic state of elevated reactive oxygen species (ROS) in pancreaticβ-cells impairs their ability to release insulin in response to elevated plasma glucose. Moreover, at its extreme, unmitigated ROS drives regulated cell death. This dysfunctional state of ROS buildup can result both from genetic predisposition and environmental factors such as obesity and overnutrition. Importantly, excessive ROS buildup may underlie metabolic pathologies such as type 2 diabetes mellitus. The ability to monitor ROS dynamics inβ-cells in situ and to manipulate it via genetic, pharmacological, and environmental means would accelerate the development of novel therapeutics that could abate this pathology. Currently, there is a lack of models with these attributes that are available to the field. In this study, we use a zebrafish model to demonstrate that ROS can be generated in aβ-cell-specific manner using a hybrid chemical genetic approach. Using a transgenic nitroreductase-expressing zebrafish line,Tg(ins:Flag-NTR)s950, treated with the prodrug metronidazole (MTZ), we found that ROS is rapidly and explicitly generated inβ-cells. Furthermore, the level of ROS generated was proportional to the dosage of prodrug added to the system. At high doses of MTZ, caspase 3 was rapidly cleaved,β-cells underwent regulated cell death, and macrophages were recruited to the islet to phagocytose the debris. Based on our findings, we propose a model for the mechanism of NTR/MTZ action in transgenic eukaryotic cells and demonstrate the robust utility of this system to model ROS-related disease pathology.

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