scholarly journals The Impact of Autophagy on Cell Death Modalities

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Stefan W. Ryter ◽  
Kenji Mizumura ◽  
Augustine M. K. Choi
Keyword(s):  
Cell Death ◽  
Inflammatory Responses ◽  
Degradation Pathway ◽  
Therapeutic Interventions ◽  
Caspase 1 ◽  
Regulated Cell Death ◽  
Caspase Inhibition ◽  
Autophagic Degradation ◽  
Dependent Cell ◽  
The Impact

Autophagy represents a homeostatic cellular mechanism for the turnover of organelles and proteins, through a lysosome-dependent degradation pathway. During starvation, autophagy facilitates cell survival through the recycling of metabolic precursors. Additionally, autophagy can modulate other vital processes such as programmed cell death (e.g., apoptosis), inflammation, and adaptive immune mechanisms and thereby influence disease pathogenesis. Selective pathways can target distinct cargoes (e.g., mitochondria and proteins) for autophagic degradation. At present, the causal relationship between autophagy and various forms of regulated or nonregulated cell death remains unclear. Autophagy can occur in association with necrosis-like cell death triggered by caspase inhibition. Autophagy and apoptosis have been shown to be coincident or antagonistic, depending on experimental context, and share cross-talk between signal transduction elements. Autophagy may modulate the outcome of other regulated forms of cell death such as necroptosis. Recent advances suggest that autophagy can dampen inflammatory responses, including inflammasome-dependent caspase-1 activation and maturation of proinflammatory cytokines. Autophagy may also act as regulator of caspase-1 dependent cell death (pyroptosis). Strategies aimed at modulating autophagy may lead to therapeutic interventions for diseases in which apoptosis or other forms of regulated cell death may play a cardinal role.

scholarly journals The STING1 network regulates autophagy and cell death

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ruoxi Zhang ◽  
Rui Kang ◽  
Daolin Tang
Keyword(s):  
Cell Death ◽  
Mitotic Cell ◽  
Therapeutic Interventions ◽  
Type I Interferons ◽  
Microbial Pathogens ◽  
Type I ◽  
Autophagic Degradation ◽  
Health And Disease ◽  
Shed Light ◽  
Pro Inflammatory Cytokines

AbstractCell death and immune response are at the core of life. In past decades, the endoplasmic reticulum (ER) protein STING1 (also known as STING or TMEM173) was found to play a fundamental role in the production of type I interferons (IFNs) and pro-inflammatory cytokines in response to DNA derived from invading microbial pathogens or damaged hosts by activating multiple transcription factors. In addition to this well-known function in infection, inflammation, and immunity, emerging evidence suggests that the STING1-dependent signaling network is implicated in health and disease by regulating autophagic degradation or various cell death modalities (e.g., apoptosis, necroptosis, pyroptosis, ferroptosis, mitotic cell death, and immunogenic cell death [ICD]). Here, we outline the latest advances in our understanding of the regulating mechanisms and signaling pathways of STING1 in autophagy and cell death, which may shed light on new targets for therapeutic interventions.

scholarly journals Asc Modulates the Function of NLRC4 in Response to Infection of Macrophages by Legionella pneumophila

mBio ◽  
2011 ◽  
Vol 2 (4) ◽  
Author(s):  
Christopher L. Case ◽  
Craig R. Roy
Keyword(s):  
Cell Death ◽  
Legionella Pneumophila ◽  
Fluorescent Protein ◽  
Microbial Infection ◽  
Content Type ◽  
Caspase 1 ◽  
Cell Death Pathway ◽  
Dependent Cell ◽  
Green Fluorescent ◽  
In Cells

ABSTRACTNucleotide-binding domain, leucine-rich repeat containing proteins (NLRs) activate caspase-1 in response to a variety of bacterium-derived signals in macrophages. NLR-mediated activation of caspase-1 byLegionella pneumophilaoccurs through both an NLRC4/NAIP5-dependent pathway and a pathway requiring the adapter protein Asc. Both pathways are needed for maximal activation of caspase-1 and for the release of the cytokines interleukin-1β (IL-1β) and IL-18. Asc is not required for caspase-1-dependent pore formation and cell death induced upon infection of macrophages byL. pneumophila. Here, temporal and spatial localization of caspase-1-dependent processes was examined to better define the roles of Asc and NLRC4 during infection. Imaging studies revealed that caspase-1 localized to a single punctate structure in infected cells containing Asc but not in cells lacking this adapter. Both endogenous Asc and ectopically produced NLRC4 tagged with green fluorescent protein (GFP) were found to localize to caspase-1 puncta followingL. pneumophilainfection, suggesting that NLRC4 and Asc coordinate signaling through this complex during caspase-1 activation. Formation of caspase-1-containing puncta correlated with caspase-1 processing, suggesting a role for the Asc/NLRC4/caspase-1 complex in caspase-1 cleavage. In cells deficient for Asc, NLRC4 did not assemble into discrete puncta, and pyroptosis occurred at an accelerated rate. These data indicate that Asc mediates integration of NLR components into caspase-1 processing platforms and that recruitment of NLR components into an Asc complex can dampen pyroptotic responses. Thus, a negative feedback role of complexes containing Asc may be important for regulating caspase-1-mediated responses during microbial infection.IMPORTANCECaspase-1 is a protease activated during infection that is central to the regulation of several innate immune pathways. Studies examining the macromolecular complexes containing this protein, known as inflammasomes, have provided insight into the regulation of this protease. This work demonstrates that the intracellular bacteriumLegionella pneumophilainduces formation of complexes containing caspase-1 by multiple mechanisms and illustrates that an adapter molecule called Asc integrates signals from multiple independent upstream caspase-1 activators in order to assemble a spatially distinct complex in the macrophage. There were caspase-1-associated activities such as cytokine processing and secretion that were controlled by Asc. Importantly, this work uncovered a new role for Asc in dampening a caspase-1-dependent cell death pathway called pyroptosis. These findings suggest that Asc plays a central role in controlling a distinct subset of caspase-1-dependent activities by both assembling complexes that are important for cytokine processing and suppressing processes that mediate pyroptosis.

scholarly journals Intracellular amyloid toxicity induces oxytosis/ferroptosis regulated cell death

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Ling Huang ◽  
Daniel B. McClatchy ◽  
Pamela Maher ◽  
Zhibin Liang ◽  
Jolene K. Diedrich ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Model ◽  
Early Stage ◽  
Metabolic Reprogramming ◽  
Therapeutic Interventions ◽  
Amyloid Toxicity ◽  
Cell Death Pathway ◽  
Regulated Cell Death ◽  
Metabolomic Data ◽  
Basic Biology

Abstract Amyloid beta (Aβ) accumulates within neurons in the brains of early stage Alzheimer’s disease (AD) patients. However, the mechanism underlying its toxicity remains unclear. Here, a triple omics approach was used to integrate transcriptomic, proteomic, and metabolomic data collected from a nerve cell model of the toxic intracellular aggregation of Aβ. It was found that intracellular Aβ induces profound changes in the omics landscape of nerve cells that are associated with a pro-inflammatory, metabolic reprogramming that predisposes cells to die via the oxytosis/ferroptosis regulated cell death pathway. Notably, the degenerative process included substantial alterations in glucose metabolism and mitochondrial bioenergetics. Our findings have implications for the understanding of the basic biology of proteotoxicity, aging, and AD as well as for the development of future therapeutic interventions designed to target the oxytosis/ferroptosis regulated cell death pathway in the AD brain.

scholarly journals Ferroptosis in plants: triggers, proposed mechanisms, and the role of iron in modulating cell death

2020 ◽  
Author(s):  
Ayelén Mariana Distéfano ◽  
Gabriel Alejandro López ◽  
Nicolás Setzes ◽  
Fernanda Marchetti ◽  
Maximiliano Cainzos ◽  
...  
Keyword(s):  
Cell Death ◽  
Metabolic Pathways ◽  
Oxygen Species ◽  
Cell Death Pathway ◽  
Plant Life ◽  
Regulated Cell Death ◽  
Dependent Cell ◽  
Plant Life Cycle ◽  
High Degree

Abstract Regulated cell death plays key roles during essential processes throughout the plant life cycle. It takes part in specific developmental programs and maintains homeostasis of the organism in response to unfavorable environments. Ferroptosis is a recently discovered iron-dependent cell death pathway characterized by the accumulation of lipid reactive oxygen species. In plants, ferroptosis shares all the main hallmarks described in other systems. Those specific features include biochemical and morphological signatures that seem to be conserved among species. However, plant cells have specific metabolic pathways and a high degree of metabolic compartmentalization. Together with their particular morphology, these features add more complexity to the plant ferroptosis pathway. In this review, we summarize the most recent advances in elucidating the roles of ferroptosis in plants, focusing on specific triggers, the main players, and underlying pathways.

scholarly journals Type I interferon signaling is required for activation of the inflammasome during Francisella infection

2007 ◽  
Vol 204 (5) ◽  
pp. 987-994 ◽  
Author(s):  
Thomas Henry ◽  
Anna Brotcke ◽  
David S. Weiss ◽  
Lucinda J. Thompson ◽  
Denise M. Monack
Keyword(s):  
Cell Death ◽  
Type I Interferon ◽  
Infection Type ◽  
Host Responses ◽  
Inflammasome Activation ◽  
Type I ◽  
Type I Ifn ◽  
Caspase 1 ◽  
Dependent Cell

Francisella tularensis is a pathogenic bacterium whose virulence is linked to its ability to replicate within the host cell cytosol. Entry into the macrophage cytosol activates a host-protective multimolecular complex called the inflammasome to release the proinflammatory cytokines interleukin (IL)-1β and -18 and trigger caspase-1–dependent cell death. In this study, we show that cytosolic F. tularensis subspecies novicida (F. novicida) induces a type I interferon (IFN) response that is essential for caspase-1 activation, inflammasome-mediated cell death, and release of IL-1β and -18. Extensive type I IFN–dependent cell death resulting in macrophage depletion occurs in vivo during F. novicida infection. Type I IFN is also necessary for inflammasome activation in response to cytosolic Listeria monocytogenes but not vacuole-localized Salmonella enterica serovar Typhimurium or extracellular adenosine triphosphate. These results show the specific connection between type I IFN signaling and inflammasome activation, which are two sequential events triggered by the recognition of cytosolic bacteria. To our knowledge, this is the first example of the positive regulation of inflammasome activation. This connection underscores the importance of the cytosolic recognition of pathogens and highlights how multiple innate immunity pathways interact before commitment to critical host responses.

scholarly journals Immune recognition of Pseudomonas aeruginosa mediated by the IPAF/NLRC4 inflammasome

2007 ◽  
Vol 204 (13) ◽  
pp. 3235-3245 ◽  
Author(s):  
Fayyaz S. Sutterwala ◽  
Lilia A. Mijares ◽  
Li Li ◽  
Yasunori Ogura ◽  
Barbara I. Kazmierczak ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Cell Death ◽  
Host Cell ◽  
Proinflammatory Cytokine ◽  
Opportunistic Infections ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Immune Recognition ◽  
Independent Manner ◽  
Caspase 1

Pseudomonas aeruginosa is a Gram-negative bacterium that causes opportunistic infections in immunocompromised individuals. P. aeruginosa employs a type III secretion system to inject effector molecules into the cytoplasm of the host cell. This interaction with the host cell leads to inflammatory responses that eventually result in cell death. We show that infection of macrophages with P. aeruginosa results in activation of caspase-1 in an IPAF-dependent, but flagellin-independent, manner. Macrophages deficient in IPAF or caspase-1 were markedly resistant to P. aeruginosa–induced cell death and release of the proinflammatory cytokine interleukin (IL)-1β. A subset of P. aeruginosa isolates express the effector molecule exoenzyme U (ExoU), which we demonstrate is capable of inhibiting caspase-1–driven proinflammatory cytokine production. This study shows a key role for IPAF and capase-1 in innate immune responses to the pathogen P. aeruginosa, and also demonstrates that virulent ExoU-expressing strains of P. aeruginosa can circumvent this innate immune response.

scholarly journals Saponin Formosanin C-Induced Ferritinophagy and Ferroptosis in Human Hepatocellular Carcinoma Cells

Antioxidants ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 682 ◽  
Author(s):  
Pin-Lun Lin ◽  
Han-Hsuan Tang ◽  
Shan-Ying Wu ◽  
Ning-Sing Shaw ◽  
Chun-Li Su
Keyword(s):  
Cell Death ◽  
Significant Negative Correlation ◽  
Degradation Pathway ◽  
Autophagic Flux ◽  
Ferritin Heavy Chain ◽  
Gfp Reporter ◽  
Dependent Cell ◽  
Ros Formation ◽  
Lc3 Puncta ◽  
Human Hepatocellular Carcinoma Cells

Ferroptosis, a recently discovered form of iron-dependent cell death, requires an increased level of lipid-reactive oxygen species (ROS). Ferritinophagy, a ferritin degradation pathway, depends on a selective autophagic cargo receptor (NCOA4). By screening various types of natural compounds, formosanin C (FC) was identified as a novel ferroptosis inducer, characterized by attenuations of FC-induced viability inhibition and lipid ROS formation in the presence of ferroptosis inhibitor. FC also induced autophagic flux, evidenced by preventing autophagic marker LC3-II degradation and increasing yellow LC3 puncta in tandem fluorescent-tagged LC3 (mRFP-GFP) reporter plasmid (ptfLC3) transfected cells when combined with autophagic flux inhibitor. It is noteworthy that FC-induced ferroptosis and autophagic flux were stronger in HepG2 cells expressing higher NCOA4 and lower ferritin heavy chain 1 (FTH1) levels, agreeing with the results of gene expression analysis using CTRP and PRISM, indicating that FTH1 expression level exhibited a significant negative correlation with the sensitivity of the cells to a ferroptosis inducer. Confocal and electron microscopy confirmed the pronounced involvement of ferritinophagy in FC-induced ferroptosis in the cells with elevated NCOA4. Since ferroptosis is a non-apoptotic form of cell death, our data suggest FC has chemotherapeutic potential against apoptosis-resistant HCC with a higher NCOA4 expression via ferritinophagy.

scholarly journals Coxiella burnetii Avirulent Nine Mile Phase II Induces Caspase-1-Dependent Pyroptosis in Murine Peritoneal B1a B Cells

2016 ◽  
Vol 84 (12) ◽  
pp. 3638-3654 ◽  
Author(s):  
Laura Schoenlaub ◽  
Rama Cherla ◽  
Yan Zhang ◽  
Guoquan Zhang
Keyword(s):  
Cell Death ◽  
Host Cell ◽  
Phase Ii ◽  
Coxiella Burnetii ◽  
Content Type ◽  
Apoptotic Signaling ◽  
Caspase 1 ◽  
B1a Cells ◽  
Dependent Cell ◽  
Toll Like Receptor 2

Our recent study demonstrated that virulentCoxiella burnetiiNine Mile phase I (NMI) is capable of infecting and replicating within peritoneal B1a cells and that B1a cells play an important role in host defense againstC. burnetiiinfection in mice. However, it remains unknown if avirulent Nine Mile phase II (NMII) can infect and replicate in B1a cells and whether NMI and NMII can differentially interact with B1a cells. In this study, we examined if NMI and NMII can differentially modulate host cell apoptotic signaling in B1a cells. The results showed that NMII induced dose-dependent cell death in murine peritoneal B1a cells but NMI did not, suggesting that NMI and NMII may differentially activate host cell apoptotic signaling in B1a cells. Western blotting indicated that NMII-induced B1a cell death was not dependent on either caspase-3 or PARP-1 cleavage, but cleavage of caspase-1 was detected in NMII-infected B1a cells. In addition, inhibition or deficiency of caspase-1 activity blocked NMII-induced B1a cell death. These results suggest that NMII induces a caspase-1-dependent pyroptosis in murine peritoneal B1a cells. We also found that heat-killed NMII and type 4 secretion system (T4SS) mutant NMII were unable to induce B1a cell death and that NMII infection did not induce cell death in peritoneal B1a cells from Toll-like receptor 2 (TLR-2)- or NLRP3 inflammasome-deficient mice. These data suggest that NMII-induced caspase-1-dependent pyroptosis may require its T4SS and activation of the TLR-2 and NLRP3 signaling pathways.

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