scholarly journals ZBP1 promotes fungi-induced inflammasome activation and pyroptosis, apoptosis, and necroptosis (PANoptosis)

2020 ◽  
Vol 295 (52) ◽  
pp. 18276-18283
Author(s):  
Balaji Banoth ◽  
Shraddha Tuladhar ◽  
Rajendra Karki ◽  
Bhesh Raj Sharma ◽  
Benoit Briard ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Fungal Pathogens ◽  
Vital Role ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Specific Cell ◽  
High Morbidity ◽  
Cell Death Pathways ◽  
Proinflammatory Responses

Candida albicans and Aspergillus fumigatus are dangerous fungal pathogens with high morbidity and mortality, particularly in immunocompromised patients. Innate immune-mediated programmed cell death (pyroptosis, apoptosis, necroptosis) is an integral part of host defense against pathogens. Inflammasomes, which are canonically formed upstream of pyroptosis, have been characterized as key mediators of fungal sensing and drivers of proinflammatory responses. However, the specific cell death pathways and key upstream sensors activated in the context of Candida and Aspergillus infections are unknown. Here, we report that C. albicans and A. fumigatus infection induced inflammatory programmed cell death in the form of pyroptosis, apoptosis, and necroptosis (PANoptosis). Further, we identified the innate immune sensor Z-DNA binding protein 1 (ZBP1) as the apical sensor of fungal infection responsible for activating the inflammasome/pyroptosis, apoptosis, and necroptosis. The Zα2 domain of ZBP1 was required to promote this inflammasome activation and PANoptosis. Overall, our results demonstrate that C. albicans and A. fumigatus induce PANoptosis and that ZBP1 plays a vital role in inflammasome activation and PANoptosis in response to fungal pathogens.

Lysosomes in programmed cell death pathways: from initiators to amplifiers

2017 ◽  
Vol 398 (3) ◽  
pp. 289-301 ◽  
Author(s):  
Nežka Kavčič ◽  
Katarina Pegan ◽  
Boris Turk
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Membrane Permeabilization ◽  
Lysosomal Membrane ◽  
Inflammasome Activation ◽  
Biological Macromolecules ◽  
Lysosomal Hydrolases ◽  
Lysosomal Membrane Permeabilization ◽  
Cell Death Pathways ◽  
Major Attention

Abstract Lysosome is the central organelle for intracellular degradation of biological macromolecules and organelles. The material destined for degradation enters the lysosomes primarily via endocytosis, autophagy and phagocytosis, and is degraded through the concerted action of more than 50 lysosomal hydrolases. However, lysosomes are also linked with numerous other processes, including cell death, inflammasome activation and immune response, as well as with lysosomal secretion and cholesterol recycling. Among them programmed cell death pathways including apoptosis have received major attention. In most of these pathways, cell death was accompanied by lysosomal membrane permeabilization and release of lysosomal constituents with an involvement of lysosomal hydrolases, including the cathepsins. However, it is less clear, whether lysosomal membrane permeabilization is really critical for the initiation of cell death programme(s). Therefore, the role of lysosomal membrane permeabilization in various programmed cell death pathways is reviewed, as well as the mechanisms leading to it.

scholarly journals Burn the house, save the day: pyroptosis in pathogen restriction

Inflammasome ◽  
2016 ◽  
Vol 2 (1) ◽  
pp. 1-6 ◽  
Author(s):  
Dave Boucher ◽  
Kaiwen W. Chen ◽  
Kate Schroder
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Cell ◽  
Innate Immune ◽  
Cytokine Storm ◽  
Cell Death Pathways ◽  
Multicellular Organisms ◽  
Pathogen Clearance ◽  
Inflammatory Caspases

AbstractMany programmed cell death pathways are essential for organogenesis, development, immunity and the maintenance of homeostasis in multicellular organisms. Pyroptosis, a highly proinflammatory form of cell death, is a critical innate immune response to prevent intracellular infection. Pyroptosis is induced upon the activation of proinflammatory caspases within macromolecular signalling platforms called inflammasomes. This article reviews our understanding of pyroptosis induction, the function of inflammatory caspases in pyroptosis execution, and the importance of pyroptosis for pathogen clearance. It also highlights the situations in which extensive pyroptosis may in fact be detrimental to the host, leading to immune cell depletion or cytokine storm. Current efforts to understand the beneficial and pathological roles of pyroptosis bring the promise of new approaches to fight infectious diseases.

scholarly journals The Molecular Links between Cell Death and Inflammasome

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1057 ◽  
Author(s):  
Kwang-Ho Lee ◽  
Tae-Bong Kang
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Current Knowledge ◽  
Protein Complexes ◽  
Death Receptor ◽  
Signaling Molecules ◽  
Inflammasome Activation ◽  
Cell Death Pathways ◽  
Wide Range ◽  
Activation Pathways

Programmed cell death pathways and inflammasome activation pathways can be genetically and functionally separated. Inflammasomes are specialized protein complexes that process pro-inflammatory cytokines, interleukin-1β (IL-1β), and IL-18 to bioactive forms for protection from a wide range of pathogens, as well as environmental and host-derived danger molecules. Programmed cell death has been extensively studied, and its role in the development, homeostasis, and control of infection and danger is widely appreciated. Apoptosis and the recently recognized necroptosis are the best-characterized forms of programmed death, and the interplay between them through death receptor signaling is also being studied. Moreover, growing evidence suggests that many of the signaling molecules known to regulate programmed cell death can also modulate inflammasome activation in a cell-intrinsic manner. Therefore, in this review, we will discuss the current knowledge concerning the role of the signaling molecules originally associated with programmed cell death in the activation of inflammasome and IL-1β processing.

scholarly journals Clinical Applications of Immunotherapy Combination Methods and New Opportunities for the Future

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Ece Esin
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Checkpoint Inhibitors ◽  
Innate Immune ◽  
Small Subset ◽  
New Class ◽  
Combination Strategies ◽  
Combination Methods ◽  
Immune Editing ◽  
Cell Death Protein

In the last decade, we have gained a deeper understanding of innate immune system. The mechanism of the continuous guarding of progressive mutations happening in a single cell was discovered and the production and the recognition of tumor associated antigens by the T-cells and elimination of numerous tumors by immune-editing were further understood. The new discoveries on immune mechanisms and its relation with carcinogenesis have led to development of a new class of drugs called immunotherapeutics. T lymphocyte-associated antigen 4, programmed cell death protein 1, and programmed cell death protein ligand 1 are the classes drugs based on immunologic manipulation and are collectively known as the “checkpoint inhibitors.” Checkpoint inhibitors have shown remarkable antitumor efficacy in a broad spectrum of malignancies; however, the strongest and most durable immune responses do not last long and the more durable responses only occur in a small subset of patients. One of the solutions which have been put forth to overcome these challenges is combination strategies. Among the dual use of methods, a backbone with either PD-1 or PD-L1 antagonist drugs alongside with certain cytotoxic chemotherapies, radiation, targeted drugs, and novel checkpoint stimulators is the most promising approach and will be on stage in forthcoming years.

Mitochondrial DNA–Related Mitochondrial Dysfunction in Neurodegenerative Diseases

2002 ◽  
Vol 126 (3) ◽  
pp. 271-280
Author(s):  
Russell H. Swerdlow
Keyword(s):  
Cell Death ◽  
Mitochondrial Dna ◽  
Programmed Cell Death ◽  
Neurodegenerative Diseases ◽  
Mitochondrial Dysfunction ◽  
Cell Lines ◽  
Late Onset ◽  
Cell Death Pathways ◽  
Mitochondrial Genotype ◽  
Cybrid Cell

Abstract Mitochondrial dysfunction occurs in several late-onset neurodegenerative diseases. Determining its origin and significance may provide insight into the pathogeneses of these disorders. Regarding origin, one hypothesis proposes mitochondrial dysfunction is driven by mitochondrial DNA (mtDNA) aberration. This hypothesis is primarily supported by data from studies of cytoplasmic hybrid (cybrid) cell lines, which facilitate the study of mitochondrial genotype-phenotype relationships. In cybrid cell lines in which mtDNA from persons with certain neurodegenerative diseases is assessed, mitochondrial physiology is altered in ways that are potentially relevant to programmed cell death pathways. Connecting mtDNA-related mitochondrial dysfunction with programmed cell death underscores the crucial if not central role for these organelles in neurodegenerative pathophysiology. This review discusses the cybrid technique and summarizes cybrid data implicating mtDNA-related mitochondrial dysfunction in certain neurodegenerative diseases.

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