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  1. Article ; Online: Luciferase-assisted detection of extracellular ATP and ATP metabolites during immunogenic death of cancer cells.

    Dubyak, George R

    Methods in enzymology

    2019  Volume 629, Page(s) 81–102

    Abstract: The efficacy of cancer chemotherapy is enhanced by induction of sustainable anti-tumor immune responses. Such responses involve accumulation of immunogenic mediators, such as extracellular ATP and ATP metabolites, within the tumor microenvironment. ... ...

    Abstract The efficacy of cancer chemotherapy is enhanced by induction of sustainable anti-tumor immune responses. Such responses involve accumulation of immunogenic mediators, such as extracellular ATP and ATP metabolites, within the tumor microenvironment. Recent studies have identified nucleotide-permeable plasma membrane channels or pores that are activated as early downstream consequences of different regulated cell death pathways: pannexin-1 channels in apoptosis, MLKL pores in necroptosis, and gasdermin-family pores in pyroptosis. This chapter describes the use of highly quantitative and semi-high-throughput methods based on the ATP sensor luciferase to measure dynamic changes in extracellular ATP, ADP, and AMP in tissue/cell culture models of cancer cells during various modes of regulated cell death in response to chemotherapeutic drugs, death receptors, or metabolic perturbation.
    MeSH term(s) Adenosine Diphosphate/analysis ; Adenosine Diphosphate/immunology ; Adenosine Diphosphate/metabolism ; Adenosine Monophosphate/analysis ; Adenosine Monophosphate/immunology ; Adenosine Monophosphate/metabolism ; Adenosine Triphosphate/analysis ; Adenosine Triphosphate/immunology ; Adenosine Triphosphate/metabolism ; Animals ; Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Apoptosis/drug effects ; Apoptosis/immunology ; Cell Line, Tumor ; Cell Membrane Permeability/immunology ; Extracellular Space/immunology ; Extracellular Space/metabolism ; Humans ; Immunogenic Cell Death/drug effects ; Luciferases/chemistry ; Membrane Transport Proteins/metabolism ; Mice ; Neoplasms/drug therapy ; Neoplasms/immunology ; Neoplasms/pathology ; Primary Cell Culture ; Pyroptosis/drug effects ; Pyroptosis/immunology ; Rats
    Chemical Substances Antineoplastic Agents ; Membrane Transport Proteins ; Adenosine Monophosphate (415SHH325A) ; Adenosine Diphosphate (61D2G4IYVH) ; Adenosine Triphosphate (8L70Q75FXE) ; Luciferases (EC 1.13.12.-)
    Language English
    Publishing date 2019-10-29
    Publishing country United States
    Document type Journal Article
    ISSN 1557-7988 ; 0076-6879
    ISSN (online) 1557-7988
    ISSN 0076-6879
    DOI 10.1016/bs.mie.2019.10.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways.

    Dubyak, George R / Miller, Brandon A / Pearlman, Eric

    Immunological reviews

    2023  Volume 314, Issue 1, Page(s) 229–249

    Abstract: Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin-family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular ... ...

    Abstract Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin-family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non-classical secretion of IL-1 family cytokines that amplify host-beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL-1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase-1 to generate GSDMD macropores that mediate IL-1β efflux and progression to pyroptotic lysis. Neutrophils, which rapidly accumulate in large numbers at sites of tissue infection or damage, become the predominant local source of IL-1β in coordination with their potent microbiocidal capacity. Similar to macrophages, neutrophils express GSDMD and utilize the same spectrum of diverse inflammasome platforms for caspase-1-mediated cleavage of GSDMD. Distinct from macrophages, neutrophils possess a remarkable capacity to resist progression to GSDMD-dependent pyroptotic lysis to preserve their viability for efficient microbial killing while maintaining GSDMD-dependent mechanisms for export of bioactive IL-1β. Rather, neutrophils employ cell-specific mechanisms to conditionally engage GSDMD-mediated pyroptosis in response to bacterial pathogens that use neutrophils as replicative niches. GSDMD and pyroptosis have also been mechanistically linked to induction of NETosis, a signature neutrophil pathway that expels decondensed nuclear DNA into extracellular compartments for immobilization and killing of microbial pathogens. This review summarizes a rapidly growing number of recent studies that have produced new insights, unexpected mechanistic nuances, and some controversies regarding the regulation of, and roles for, neutrophil inflammasomes, pyroptosis, and GSDMs in diverse innate immune responses.
    MeSH term(s) Humans ; Pyroptosis/physiology ; Inflammasomes/metabolism ; Neutrophils ; Intracellular Signaling Peptides and Proteins/metabolism ; Gasdermins ; Caspase 1/metabolism ; Signal Transduction
    Chemical Substances Inflammasomes ; Intracellular Signaling Peptides and Proteins ; Gasdermins ; Caspase 1 (EC 3.4.22.36)
    Language English
    Publishing date 2023-01-19
    Publishing country England
    Document type Journal Article ; Review ; Research Support, N.I.H., Extramural
    ZDB-ID 391796-4
    ISSN 1600-065X ; 0105-2896
    ISSN (online) 1600-065X
    ISSN 0105-2896
    DOI 10.1111/imr.13186
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Pyroptosis in neutrophils: Multimodal integration of inflammasome and regulated cell death signaling pathways

    Dubyak, George R. / Miller, Brandon A. / Pearlman, Eric

    Immunological Reviews 2023 Mar., v. 314, no. 1, p. 229-249

    2023  , Page(s) 229–249

    Abstract: Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin‐family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular ... ...

    Abstract Pyroptosis is a proinflammatory mode of lytic cell death mediated by accumulation of plasma membrane (PM) macropores composed of gasdermin‐family (GSDM) proteins. It facilitates two major functions in innate immunity: (i) elimination of intracellular replicative niches for pathogenic bacteria; and (ii) non‐classical secretion of IL‐1 family cytokines that amplify host‐beneficial inflammatory responses to microbial infection or tissue damage. Physiological roles for gasdermin D (GSDMD) in pyroptosis and IL‐1β release during inflammasome signaling have been extensively characterized in macrophages. This involves cleavage of GSDMD by caspase‐1 to generate GSDMD macropores that mediate IL‐1β efflux and progression to pyroptotic lysis. Neutrophils, which rapidly accumulate in large numbers at sites of tissue infection or damage, become the predominant local source of IL‐1β in coordination with their potent microbiocidal capacity. Similar to macrophages, neutrophils express GSDMD and utilize the same spectrum of diverse inflammasome platforms for caspase‐1‐mediated cleavage of GSDMD. Distinct from macrophages, neutrophils possess a remarkable capacity to resist progression to GSDMD‐dependent pyroptotic lysis to preserve their viability for efficient microbial killing while maintaining GSDMD‐dependent mechanisms for export of bioactive IL‐1β. Rather, neutrophils employ cell‐specific mechanisms to conditionally engage GSDMD‐mediated pyroptosis in response to bacterial pathogens that use neutrophils as replicative niches. GSDMD and pyroptosis have also been mechanistically linked to induction of NETosis, a signature neutrophil pathway that expels decondensed nuclear DNA into extracellular compartments for immobilization and killing of microbial pathogens. This review summarizes a rapidly growing number of recent studies that have produced new insights, unexpected mechanistic nuances, and some controversies regarding the regulation of, and roles for, neutrophil inflammasomes, pyroptosis, and GSDMs in diverse innate immune responses.
    Keywords caspase-1 ; exports ; inflammasomes ; innate immunity ; interleukin-1 ; macrophages ; macropores ; neutrophils ; nuclear genome ; plasma membrane ; pyroptosis ; secretion ; viability
    Language English
    Dates of publication 2023-03
    Size p. 229-249
    Publishing place John Wiley & Sons, Inc
    Document type Article ; Online
    Note REVIEW ; Resource is Open Access ; Wiley License Information
    ZDB-ID 391796-4
    ISSN 1600-065X ; 0105-2896
    ISSN (online) 1600-065X
    ISSN 0105-2896
    DOI 10.1111/imr.13186
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  4. Article ; Online: Microbes mediate mitochondrial misinformation to misguide neutrophils.

    Karmakar, Mausita / Dubyak, George R

    Journal of leukocyte biology

    2019  Volume 106, Issue 6, Page(s) 1197–1200

    Abstract: Discussion on LPS disruption of mitochondrial localization and autocrine purinergic signaling in neutrophil chemotaxis for control of E. coli infection. ...

    Abstract Discussion on LPS disruption of mitochondrial localization and autocrine purinergic signaling in neutrophil chemotaxis for control of E. coli infection.
    MeSH term(s) Anti-Infective Agents ; Chemotaxis ; Communication ; Escherichia coli ; Lipopolysaccharides ; Neutrophils
    Chemical Substances Anti-Infective Agents ; Lipopolysaccharides
    Language English
    Publishing date 2019-10-21
    Publishing country United States
    Document type Editorial ; Comment
    ZDB-ID 605722-6
    ISSN 1938-3673 ; 0741-5400
    ISSN (online) 1938-3673
    ISSN 0741-5400
    DOI 10.1002/JLB.3CE0819-263
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  5. Article ; Online: Gasdermins and pannexin-1 mediate pathways of chemotherapy-induced cell lysis in hematopoietic malignancies.

    Zhou, Bowen / Ryder, Christopher B / Dubyak, George R / Abbott, Derek W

    Science signaling

    2022  Volume 15, Issue 765, Page(s) eabl6781

    Abstract: Pyroptosis is a mechanism of programmed, necrotic cell death mediated by gasdermins, a family of pore-forming proteins. Caspase-1 activates gasdermin D (GSDMD) under inflammatory conditions, whereas caspase-3 activates GSDME under apoptotic conditions, ... ...

    Abstract Pyroptosis is a mechanism of programmed, necrotic cell death mediated by gasdermins, a family of pore-forming proteins. Caspase-1 activates gasdermin D (GSDMD) under inflammatory conditions, whereas caspase-3 activates GSDME under apoptotic conditions, such as those induced by chemotherapy. These pathways are thought to be separate. However, we found that they are part of an integrated network of gatekeepers that enables pyroptotic cell death. We observed that GSDMD was the primary pyroptotic mediator in cultured blood cells in response to doxorubicin and etoposide, two common chemotherapies for hematopoietic malignancies. Upon treatment, the channel protein pannexin-1 (PANX1), which is stimulated by the initiation of apoptosis, increased membrane permeability to induce K
    MeSH term(s) Humans ; Gasdermins ; Intracellular Signaling Peptides and Proteins/metabolism ; Apoptosis ; Necrosis ; Inflammasomes/metabolism ; Hematologic Neoplasms ; Antineoplastic Agents ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Connexins/genetics ; Connexins/metabolism
    Chemical Substances Gasdermins ; Intracellular Signaling Peptides and Proteins ; Inflammasomes ; Antineoplastic Agents ; PANX1 protein, human ; Nerve Tissue Proteins ; Connexins
    Language English
    Publishing date 2022-12-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2417226-1
    ISSN 1937-9145 ; 1945-0877
    ISSN (online) 1937-9145
    ISSN 1945-0877
    DOI 10.1126/scisignal.abl6781
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Protein engineering reveals that gasdermin A preferentially targets mitochondrial membranes over the plasma membrane during pyroptosis.

    Kondolf, Hannah C / D'Orlando, Dana A / Dubyak, George R / Abbott, Derek W

    The Journal of biological chemistry

    2023  Volume 299, Issue 2, Page(s) 102908

    Abstract: When activated, gasdermin family members are thought to be pore-forming proteins that cause lytic cell death. Despite this, numerous studies have suggested that the threshold for lytic cell death is dependent on which gasdermin family member is activated. ...

    Abstract When activated, gasdermin family members are thought to be pore-forming proteins that cause lytic cell death. Despite this, numerous studies have suggested that the threshold for lytic cell death is dependent on which gasdermin family member is activated. Determination of the propensity of various gasdermin family members to cause pyroptosis has been handicapped by the fact that for many of them, the mechanisms and timing of their activation are uncertain. In this article, we exploit the recently discovered exosite-mediated recognition of gasdermin D (GSDMD) by the inflammatory caspases to develop a system that activates gasdermin family members in an efficient and equivalent manner. We leverage this system to show that upon activation, GSDMD and gasdermin A (GSDMA) exhibit differential subcellular localization, differential plasma membrane permeabilization, and differential lytic cell death. While GSDMD localizes rapidly to both the plasma membrane and organelle membranes, GSDMA preferentially localizes to the mitochondria with delayed and diminished accumulation at the plasma membrane. As a consequence of this differential kinetics of subcellular localization, N-terminal GSDMA results in early mitochondrial dysfunction relative to plasma membrane permeabilization. This study thus challenges the assumption that gasdermin family members effect cell death through identical mechanisms and establishes that their activation in their respective tissues of expression likely results in different immunological outcomes.
    MeSH term(s) Pyroptosis ; Gasdermins ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Intracellular Signaling Peptides and Proteins/metabolism ; Mitochondrial Membranes/metabolism ; Phosphate-Binding Proteins/metabolism ; Cell Membrane/metabolism ; Inflammasomes/metabolism ; Protein Engineering
    Chemical Substances Gasdermins ; Neoplasm Proteins ; Intracellular Signaling Peptides and Proteins ; Phosphate-Binding Proteins ; Inflammasomes
    Language English
    Publishing date 2023-01-13
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2023.102908
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  7. Article ; Online: Lysosomal disruption by orthopedic wear particles induces activation of the NLRP3 inflammasome and macrophage cell death by distinct mechanisms.

    Fort, Brian P / Dubyak, George R / Greenfield, Edward M

    Journal of orthopaedic research : official publication of the Orthopaedic Research Society

    2020  Volume 39, Issue 3, Page(s) 493–505

    Abstract: Wear particles from orthopedic implants cause aseptic loosening, the leading cause of implant revisions. The particles are phagocytosed by macrophages leading to activation of the nod-like receptor protein 3 (NLRP3) inflammasome and release of ... ...

    Abstract Wear particles from orthopedic implants cause aseptic loosening, the leading cause of implant revisions. The particles are phagocytosed by macrophages leading to activation of the nod-like receptor protein 3 (NLRP3) inflammasome and release of interleukin-1β (IL-1β) which then contributes to osteoclast differentiation and implant loosening. The mechanism of inflammasome activation by orthopedic particles is undetermined but other particles cause the cytosolic accumulation of the lysosomal cathepsin-family proteases which can activate the NLRP3 inflammasome. Here, we demonstrate that lysosome membrane disruption causes cathepsin release into the cytoplasm that drives both inflammasome activation and cell death but that these processes occur independently. Using wild-type and genetically-manipulated immortalized murine bone marrow derived macrophages and pharmacologic inhibitors, we found that NLRP3 and gasdermin D are required for particle-induced IL-1β release but not for particle-induced cell death. In contrast, phagocytosis and lysosomal cathepsin release are critical for both IL-1β release and cell death. Collectively, our findings identify the pan-cathepsin inhibitor Ca-074Me and the NLRP3 inflammasome inhibitor MCC950 as therapeutic interventions worth exploring in aseptic loosening of orthopedic implants. We also found that particle-induced activation of the NLRP3 inflammasome in pre-primed macrophages and cell death are not dependent on pathogen-associated molecular patterns adherent to the wear particles despite such pathogen-associated molecular patterns being critical for all other previously studied wear particle responses, including priming of the NLRP3 inflammasome.
    MeSH term(s) Cathepsins/metabolism ; Cell Death ; Humans ; Interleukin-1beta/metabolism ; Lysosomes/metabolism ; NLR Family, Pyrin Domain-Containing 3 Protein/metabolism ; Pathogen-Associated Molecular Pattern Molecules ; Phagocytosis ; Prosthesis Failure/etiology ; Titanium
    Chemical Substances Interleukin-1beta ; NLR Family, Pyrin Domain-Containing 3 Protein ; Pathogen-Associated Molecular Pattern Molecules ; Titanium (D1JT611TNE) ; Cathepsins (EC 3.4.-)
    Language English
    Publishing date 2020-08-22
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 605542-4
    ISSN 1554-527X ; 0736-0266
    ISSN (online) 1554-527X
    ISSN 0736-0266
    DOI 10.1002/jor.24826
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  8. Article ; Online: Dueling nucleosides: cross-regulation of extracellular adenosine by guanosine. Focus on "Extracellular guanosine regulates extracellular adenosine levels".

    Dubyak, George R

    American journal of physiology. Cell physiology

    2013  Volume 304, Issue 5, Page(s) C403–5

    MeSH term(s) Adenosine/metabolism ; Animals ; Guanosine/metabolism ; Humans ; Male ; Muscle, Smooth, Vascular/metabolism ; Myocytes, Smooth Muscle/metabolism
    Chemical Substances Guanosine (12133JR80S) ; Adenosine (K72T3FS567)
    Language English
    Publishing date 2013-01-16
    Publishing country United States
    Document type Editorial ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 392098-7
    ISSN 1522-1563 ; 0363-6143
    ISSN (online) 1522-1563
    ISSN 0363-6143
    DOI 10.1152/ajpcell.00012.2013
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  9. Article ; Online: Function without form: an ongoing search for maxi-anion channel proteins. Focus on "Maxi-anion channel and pannexin 1 hemichannel constitute separate pathways for swelling-induced ATP release in murine L929 fibrosarcoma cells".

    Dubyak, George R

    American journal of physiology. Cell physiology

    2012  Volume 303, Issue 9, Page(s) C913–5

    MeSH term(s) Adenosine Triphosphate/metabolism ; Animals ; Chloride Channels/physiology ; Connexins/physiology ; Nerve Tissue Proteins/physiology
    Chemical Substances Chloride Channels ; Connexins ; Nerve Tissue Proteins ; Panx1 protein, mouse ; Adenosine Triphosphate (8L70Q75FXE)
    Language English
    Publishing date 2012-08-29
    Publishing country United States
    Document type Editorial ; Research Support, N.I.H., Extramural ; Comment
    ZDB-ID 392098-7
    ISSN 1522-1563 ; 0363-6143
    ISSN (online) 1522-1563
    ISSN 0363-6143
    DOI 10.1152/ajpcell.00285.2012
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  10. Article ; Online: P2X7 receptor regulation of non-classical secretion from immune effector cells.

    Dubyak, George R

    Cellular microbiology

    2012  Volume 14, Issue 11, Page(s) 1697–1706

    Abstract: P2X7 receptors (P2X7R) are extracellular ATP-gated ion channels expressed in the immune effector cells that carry out critical protective responses during the early phases of microbial infection or acute tissue trauma. P2X7R-positive cells include ... ...

    Abstract P2X7 receptors (P2X7R) are extracellular ATP-gated ion channels expressed in the immune effector cells that carry out critical protective responses during the early phases of microbial infection or acute tissue trauma. P2X7R-positive cells include monocytes, macrophages, dendritic cells and T cells. Given its presence in all host and pathogen cell types, ATP can be readily released into extracellular compartments at local sites of tissue damage and microbial invasion. Thus, extracellular ATP and its target receptors on host effector cells can be considered as additional elements of the innate immune system. In this regard, stimulation of P2X7R rapidly triggers a key step of the inflammatory response: induction of NLRP3/caspase-1 inflammasome signalling complexes that drive the proteolytic maturation and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18). IL-1β (and IL-18) lacks a signal sequence for compartmentation within the Golgi and classical secretory vesicles and the proIL-1β precursor accumulates within the cytosol following translation on free ribosomes. Thus, ATP-induced accumulation of the mature IL-1β cytokine within extracellular compartments requires non-classical mechanisms of export from the cytosolic compartment. Five proposed mechanisms include: (i) exocytosis of secretory lysosomes that accumulate cytosolic IL-1β via undefined protein transporters; (ii) release of membrane-delimited microvesicles derived from plasma membrane blebs formed by evaginationsof the surface membrane that entrap cytosolic IL-β; (iii) release of membrane-delimited exosomes secondary to the exocytosis of multivesicular bodies formed by invaginations of recycling endosomes that entrap cytosolic IL-β; (iv) exocytosis of autophagosomes or autophagolysosomes that accumulate cytosolic IL-1β via entrapment during formation of the initial autophagic isolation membrane or omegasome and (v) direct release of cytosolic IL-1β secondary to regulated cell death by pyroptosis or necroptosis. These mechanisms are not mutually exclusive and may represent engagement of parallel or intersecting membrane trafficking responses to P2X7R activation.
    MeSH term(s) Adenosine Triphosphate/metabolism ; Animals ; Cytokines/metabolism ; Dendritic Cells/immunology ; Humans ; Macrophages/immunology ; Models, Biological ; Monocytes/immunology ; Receptors, Purinergic P2X7/metabolism ; T-Lymphocytes/immunology
    Chemical Substances Cytokines ; Receptors, Purinergic P2X7 ; Adenosine Triphosphate (8L70Q75FXE)
    Language English
    Publishing date 2012-08-24
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Review
    ZDB-ID 1468320-9
    ISSN 1462-5822 ; 1462-5814
    ISSN (online) 1462-5822
    ISSN 1462-5814
    DOI 10.1111/cmi.12001
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