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  1. Article ; Online: Generation of Casp8FL122/123GG Mice Using CRISPR-Cas9 Technology

    Stephane Pelletier / Bart Tummers / Douglas R. Green

    STAR Protocols, Vol 1, Iss 3, Pp 100181- (2020)

    2020  

    Abstract: Summary: The purpose of this protocol is to describe the generation of missense mutations in mice using CRISPR-Cas9 technology. The current protocol focuses on the generation of a Casp8FL122/123GG missense mutation, but it can be adapted to introduce any ...

    Abstract Summary: The purpose of this protocol is to describe the generation of missense mutations in mice using CRISPR-Cas9 technology. The current protocol focuses on the generation of a Casp8FL122/123GG missense mutation, but it can be adapted to introduce any missense or nonsense mutation.For complete details on the use and execution of this protocol, please refer to Tummers et al. (2020).
    Keywords Model Organisms ; CRISPR ; Science (General) ; Q1-390
    Language English
    Publishing date 2020-12-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Dynamic metabolic reprogramming in dendritic cells

    Svetlana Rezinciuc / Lavanya Bezavada / Azadeh Bahadoran / Susu Duan / Ruoning Wang / Daniel Lopez-Ferrer / David Finkelstein / Maureen A McGargill / Douglas R Green / Ljiljana Pasa-Tolic / Heather S Smallwood

    PLoS Pathogens, Vol 16, Iss 10, p e

    An early response to influenza infection that is essential for effector function.

    2020  Volume 1008957

    Abstract: Infection with the influenza virus triggers an innate immune response that initiates the adaptive response to halt viral replication and spread. However, the metabolic response fueling the molecular mechanisms underlying changes in innate immune cell ... ...

    Abstract Infection with the influenza virus triggers an innate immune response that initiates the adaptive response to halt viral replication and spread. However, the metabolic response fueling the molecular mechanisms underlying changes in innate immune cell homeostasis remain undefined. Although influenza increases parasitized cell metabolism, it does not productively replicate in dendritic cells. To dissect these mechanisms, we compared the metabolism of dendritic cells to that of those infected with active and inactive influenza A virus and those treated with toll-like receptor agonists. Using quantitative mass spectrometry, pulse chase substrate utilization assays and metabolic flux measurements, we found global metabolic changes in dendritic cells 17 hours post infection, including significant changes in carbon commitment via glycolysis and glutaminolysis, as well as mitochondrial respiration. Influenza infection of dendritic cells led to a metabolic phenotype distinct from that induced by TLR agonists, with significant resilience in terms of metabolic plasticity. We identified c-Myc as one transcription factor modulating this response. Restriction of c-Myc activity or mitochondrial substrates significantly changed the immune functions of dendritic cells, such as reducing motility and T cell activation. Transcriptome analysis of inflammatory dendritic cells isolated following influenza infection showed similar metabolic reprogramming occurs in vivo. Thus, early in the infection process, dendritic cells respond with global metabolic restructuring, that is present in inflammatory lung dendritic cells after infection, and this is important for effector function. These findings suggest metabolic switching in dendritic cells plays a vital role in initiating the immune response to influenza infection.
    Keywords Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2020-10-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article: Developmental checkpoints guarded by regulated necrosis

    Dillon, Christopher P / Bart Tummers / Katherine Baran / Douglas R. Green

    Cellular and molecular life sciences. 2016 June, v. 73, no. 11-12

    2016  

    Abstract: The process of embryonic development is highly regulated through the symbiotic control of differentiation and programmed cell death pathways, which together sculpt tissues and organs. The importance of programmed necrotic (RIPK-dependent necroptosis) ... ...

    Abstract The process of embryonic development is highly regulated through the symbiotic control of differentiation and programmed cell death pathways, which together sculpt tissues and organs. The importance of programmed necrotic (RIPK-dependent necroptosis) cell death during development has recently been recognized as important and has largely been characterized using genetically engineered animals. Suppression of necroptosis appears to be essential for murine development and occurs at three distinct checkpoints, E10.5, E16.5, and P1. These distinct time points have helped delineate the molecular pathways and regulation of necroptosis. The embryonic lethality at E10.5 seen in knockouts of caspase-8, FADD, or FLIP (cflar), components of the extrinsic apoptosis pathway, resulted in pallid embryos that did not exhibit the expected cellular expansions. This was the first suggestion that these factors play an important role in the inhibition of necroptotic cell death. The embryonic lethality at E16.5 highlighted the importance of TNF engaging necroptosis in vivo, since elimination of TNFR1 from casp8 ⁻/⁻, fadd ⁻/⁻, or cflar ⁻/⁻, ripk3 ⁻/⁻ embryos delayed embryonic lethality from E10.5 until E16.5. The P1 checkpoint demonstrates the dual role of RIPK1 in both the induction and inhibition of necroptosis, depending on the upstream signal. This review summarizes the role of necroptosis in development and the genetic evidence that helped detail the molecular mechanisms of this novel pathway of programmed cell death.
    Keywords apoptosis ; caspase-8 ; embryogenesis ; mice ; necrosis ; tissues ; transgenic animals ; tumor necrosis factors
    Language English
    Dates of publication 2016-06
    Size p. 2125-2136.
    Publishing place Springer International Publishing
    Document type Article
    Note Review
    ZDB-ID 1358415-7
    ISSN 1420-9071 ; 1420-682X
    ISSN (online) 1420-9071
    ISSN 1420-682X
    DOI 10.1007/s00018-016-2188-z
    Database NAL-Catalogue (AGRICOLA)

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    Z 4' 47/14: Show issues

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  4. Article ; Online: Stress and the Control of Apoptosis

    Douglas R. Green

    The Scientific World Journal, Vol 1, Pp 47-

    2001  Volume 47

    Keywords Technology ; T ; Medicine ; R ; Science ; Q
    Language English
    Publishing date 2001-01-01T00:00:00Z
    Publisher Hindawi Limited
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article: Many players in BCL-2 family affairs

    Moldoveanu, Tudor / Ariele Viacava Follis / Richard W. Kriwacki / Douglas R. Green

    Trends in biochemical sciences. 2014 Mar., v. 39

    2014  

    Abstract: During apoptotic cell death, cellular stress signals converge at the mitochondria to induce mitochondrial outer-membrane permeabilization (MOMP) through B cell lymphoma-2 (BCL-2) family proteins and their effectors. BCL-2 proteins function through ... ...

    Abstract During apoptotic cell death, cellular stress signals converge at the mitochondria to induce mitochondrial outer-membrane permeabilization (MOMP) through B cell lymphoma-2 (BCL-2) family proteins and their effectors. BCL-2 proteins function through protein–protein interactions, the mechanisms and structural aspects of which are only now being uncovered. Recently, the elucidation of the dynamic features underlying their function has highlighted their structural plasticity and the consequent complex thermodynamic landscape governing their protein–protein interactions. These studies show that canonical interactions involve a conserved, hydrophobic groove, whereas non-canonical interactions function allosterically outside the groove. We review the latest structural advances in understanding the interactions and functions of mammalian BCL-2 family members, and discuss new opportunities to modulate these proteins in health and disease.
    Keywords apoptosis ; hydrophobicity ; landscapes ; mammals ; mitochondria ; protein-protein interactions ; proteins ; thermodynamics
    Language English
    Dates of publication 2014-03
    Size p. 101-111.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 194220-7
    ISSN 0968-0004 ; 0376-5067
    ISSN 0968-0004 ; 0376-5067
    DOI 10.1016/j.tibs.2013.12.006
    Database NAL-Catalogue (AGRICOLA)

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    Z 78/716: Show issues

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  6. Article: ESCRT-III Acts Downstream of MLKL to Regulate Necroptotic Cell Death and Its Consequences

    Gong, Yi-Nan / Andreas Linkermann / Cliff Guy / Douglas R. Green / Hannes Olauson / Jan Ulrich Becker / Mao Yang / Patrick Fitzgerald

    Cell. 2017 Apr. 06, v. 169

    2017  

    Abstract: The activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated necrosis, called necroptosis. Here, we show that, during necroptosis, MLKL-dependent ... ...

    Abstract The activation of mixed lineage kinase-like (MLKL) by receptor-interacting protein kinase-3 (RIPK3) results in plasma membrane (PM) disruption and a form of regulated necrosis, called necroptosis. Here, we show that, during necroptosis, MLKL-dependent calcium (Ca2+) influx and phosphatidylserine (PS) exposure on the outer leaflet of the plasma membrane preceded loss of PM integrity. Activation of MLKL results in the generation of broken, PM “bubbles” with exposed PS that are released from the surface of the otherwise intact cell. The ESCRT-III machinery is required for formation of these bubbles and acts to sustain survival of the cell when MLKL activation is limited or reversed. Under conditions of necroptotic cell death, ESCRT-III controls the duration of plasma membrane integrity. As a consequence of the action of ESCRT-III, cells undergoing necroptosis can express chemokines and other regulatory molecules and promote antigenic cross-priming of CD8+ T cells.
    Keywords bubbles ; calcium ; CD8-positive T-lymphocytes ; chemokines ; necrosis ; phosphatidylserines ; plasma membrane
    Language English
    Dates of publication 2017-0406
    Size p. 286-300.e16.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 187009-9
    ISSN 1097-4172 ; 0092-8674
    ISSN (online) 1097-4172
    ISSN 0092-8674
    DOI 10.1016/j.cell.2017.03.020
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    Z 93: Show issues

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  7. Article ; Online: RIPK3 Activation Leads to Cytokine Synthesis that Continues after Loss of Cell Membrane Integrity

    Susana L. Orozco / Brian P. Daniels / Nader Yatim / Michelle N. Messmer / Giovanni Quarato / Haiyin Chen-Harris / Sean P. Cullen / Annelise G. Snyder / Pooja Ralli-Jain / Sharon Frase / Stephen W.G. Tait / Douglas R. Green / Matthew L. Albert / Andrew Oberst

    Cell Reports, Vol 28, Iss 9, Pp 2275-2287.e

    2019  Volume 5

    Abstract: Summary: Necroptosis is a form of programmed cell death that is defined by activation of the kinase RIPK3 and subsequent cell membrane permeabilization by the effector MLKL. RIPK3 activation can also promote immune responses via production of cytokines ... ...

    Abstract Summary: Necroptosis is a form of programmed cell death that is defined by activation of the kinase RIPK3 and subsequent cell membrane permeabilization by the effector MLKL. RIPK3 activation can also promote immune responses via production of cytokines and chemokines. How active cytokine production is coordinated with the terminal process of necroptosis is unclear. Here, we report that cytokine production continues within necroptotic cells even after they have lost cell membrane integrity and irreversibly committed to death. This continued cytokine production is dependent on mRNA translation and requires maintenance of endoplasmic reticulum integrity that remains after plasma membrane integrity is lost. The continued translation of cytokines by cellular corpses contributes to necroptotic cell uptake by innate immune cells and priming of adaptive immune responses to antigens associated with necroptotic corpses. These findings imply that cell death and production of inflammatory mediators are coordinated to optimize the immunogenicity of necroptotic cells. : Necroptotic cell death is associated with cytokine production. Orozco et al. show that necroptotic cell “corpses” continue to synthesize cytokines after they have lost membrane integrity and committed to cell death. This activity involves continued mRNA translation and requires ER function that continues after plasma membrane rupture. Keywords: necroptosis, cell death, phagocytosis, cytokines, RIPK3, MLKL
    Keywords Biology (General) ; QH301-705.5
    Subject code 571
    Language English
    Publishing date 2019-08-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  8. Article ; Online: Autophagy Controls the Kinetics and Extent of Mitochondrial Apoptosis by Regulating PUMA Levels

    Jacqueline Thorburn / Zdenek Andrysik / Leah Staskiewicz / Jacob Gump / Paola Maycotte / Andrew Oberst / Douglas R. Green / Joaquín M. Espinosa / Andrew Thorburn

    Cell Reports, Vol 7, Iss 1, Pp 45-

    2014  Volume 52

    Abstract: Macroautophagy is thought to protect against apoptosis; however, underlying mechanisms are poorly understood. We examined how autophagy affects canonical death receptor-induced mitochondrial outer membrane permeabilization (MOMP) and apoptosis. MOMP ... ...

    Abstract Macroautophagy is thought to protect against apoptosis; however, underlying mechanisms are poorly understood. We examined how autophagy affects canonical death receptor-induced mitochondrial outer membrane permeabilization (MOMP) and apoptosis. MOMP occurs at variable times in a population of cells, and this is delayed by autophagy. Additionally, autophagy leads to inefficient MOMP, after which some cells die through a slower process than typical apoptosis and, surprisingly, can recover and divide afterward. These effects are associated with p62/SQSTM1-dependent selective autophagy causing PUMA levels to be kept low through an indirect mechanism whereby autophagy affects constitutive levels of PUMA mRNA. PUMA depletion is sufficient to prevent the sensitization to apoptosis that occurs when autophagy is blocked. Autophagy can therefore control apoptosis via a key regulator that makes MOMP faster and more efficient, thus ensuring rapid completion of apoptosis. This identifies a molecular mechanism whereby cell-fate decisions can be determined by autophagy.
    Keywords Biology (General) ; QH301-705.5
    Subject code 610
    Language English
    Publishing date 2014-04-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article: Sequential Engagement of Distinct MLKL Phosphatidylinositol-Binding Sites Executes Necroptosis

    Quarato, Giovanni / Amanda Nourse / Christy R. Grace / Cliff S. Guy / Diego A. Rodriguez / Douglas R. Green / Fabien Llambi / Randall Wakefield / Sharon Frase / Tudor Moldoveanu

    Molecular cell. 2016 Feb. 18, v. 61, no. 4

    2016  

    Abstract: Necroptosis is a cell death pathway regulated by the receptor interacting protein kinase 3 (RIPK3) and the mixed lineage kinase domain-like (MLKL) pseudokinase. How MLKL executes plasma membrane rupture upon phosphorylation by RIPK3 remains controversial. ...

    Abstract Necroptosis is a cell death pathway regulated by the receptor interacting protein kinase 3 (RIPK3) and the mixed lineage kinase domain-like (MLKL) pseudokinase. How MLKL executes plasma membrane rupture upon phosphorylation by RIPK3 remains controversial. Here, we characterize the hierarchical transduction of structural changes in MLKL that culminate in necroptosis. The MLKL brace, proximal to the N-terminal helix bundle (NB), is involved in oligomerization to facilitate plasma membrane targeting through the low-affinity binding of NB to phosphorylated inositol polar head groups of phosphatidylinositol phosphate (PIP) phospholipids. At the membrane, the NB undergoes a “rolling over” mechanism to expose additional higher-affinity PIP-binding sites responsible for robust association to the membrane and displacement of the brace from the NB. PI(4,5)P2 is the preferred PIP-binding partner. We investigate the specific association of MLKL with PIPs and subsequent structural changes during necroptosis.
    Keywords cell death ; inositols ; oligomerization ; phosphates ; phospholipids ; phosphorylation ; plasma membrane
    Language English
    Dates of publication 2016-0218
    Size p. 589-601.
    Publishing place Elsevier Inc.
    Document type Article
    ZDB-ID 1415236-8
    ISSN 1097-4164 ; 1097-2765
    ISSN (online) 1097-4164
    ISSN 1097-2765
    DOI 10.1016/j.molcel.2016.01.011
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    Z 2005/501: Show issues

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  10. Article ; Online: Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation

    Gaojian Lian / JN Rashida Gnanaprakasam / Tingting Wang / Ruohan Wu / Xuyong Chen / Lingling Liu / Yuqing Shen / Mao Yang / Jun Yang / Ying Chen / Vasilis Vasiliou / Teresa A Cassel / Douglas R Green / Yusen Liu / Teresa WM Fan / Ruoning Wang

    eLife, Vol

    2018  Volume 7

    Abstract: Upon antigen stimulation, T lymphocytes undergo dramatic changes in metabolism to fulfill the bioenergetic, biosynthetic and redox demands of proliferation and differentiation. Glutathione (GSH) plays an essential role in controlling redox balance and ... ...

    Abstract Upon antigen stimulation, T lymphocytes undergo dramatic changes in metabolism to fulfill the bioenergetic, biosynthetic and redox demands of proliferation and differentiation. Glutathione (GSH) plays an essential role in controlling redox balance and cell fate. While GSH can be recycled from Glutathione disulfide (GSSG), the inhibition of this recycling pathway does not impact GSH content and murine T cell fate. By contrast, the inhibition of the de novo synthesis of GSH, by deleting either the catalytic (Gclc) or the modifier (Gclm) subunit of glutamate–cysteine ligase (Gcl), dampens intracellular GSH, increases ROS, and impact T cell differentiation. Moreover, the inhibition of GSH de novo synthesis dampened the pathological progression of experimental autoimmune encephalomyelitis (EAE). We further reveal that glutamine provides essential precursors for GSH biosynthesis. Our findings suggest that glutamine catabolism fuels de novo synthesis of GSH and directs the lineage choice in T cells.
    Keywords T cells ; ROS ; glutathione ; activation ; differentiation ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
    Subject code 580
    Language English
    Publishing date 2018-09-01T00:00:00Z
    Publisher eLife Sciences Publications Ltd
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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