Accidental Activation

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William T. Garrard - One of the best experts on this subject based on the ideXlab platform.

  • Discovery, regulation, and action of the major apoptotic nucleases DFF40/CAD and endonuclease G.
    Journal of cellular biochemistry, 2005
    Co-Authors: Piotr Widlak, William T. Garrard
    Abstract:

    Toward the end of the 20th and beginning of the 21st centuries, clever in vitro biochemical complementation experiments and genetic screens from the laboratories of Xiaodong Wang, Shigekazu Nagata, and Ding Xue led to the discovery of two major apoptotic nucleases, termed DNA fragmentation factor (DFF) or caspase-activated DNase (CAD) and endonuclease G (Endo G). Both endonucleases attack chromatin to yield 3′-hydroxyl groups and 5′-phosphate residues, first at the level of 50–300 kb cleavage products and next at the level of internucleosomal DNA fragmentation, but these nucleases possess completely different cellular locations in normal cells and are regulated in vastly different ways. In non-apoptotic cells, DFF exists in the nucleus as a heterodimer, composed of a 45 kD chaperone and inhibitor subunit (DFF45) [also called inhibitor of CAD (ICAD-L)] and a 40 kD latent nuclease subunit (DFF40/CAD). Apoptotic Activation of caspase-3 or -7 results in the cleavage of DFF45/ICAD and release of active DFF40/CAD nuclease. DFF40's nuclease activity is further activated by specific chromosomal proteins, such as histone H1, HMGB1/2, and topoisomerase II. DFF is regulated by multiple pre- and post-Activation fail-safe steps, which include the requirements for DFF45/ICAD, Hsp70, and Hsp40 proteins to mediate appropriate folding during translation to generate a potentially activatable nuclease, and the synthesis in stoichiometric excess of the inhibitors (DFF45/35; ICAD-S/L). By contrast, Endo G resides in the mitochondrial intermembrane space in normal cells, and is released into the nucleus upon apoptotic disruption of mitochondrial membrane permeability in association with co-activators such as apoptosis-inducing factor (AIF). Understanding further regulatory check-points involved in safeguarding non-apoptotic cells against Accidental Activation of these nucleases remain as future challenges, as well as designing ways to selectively activate these nucleases in tumor cells. © 2005 Wiley-Liss, Inc.

  • discovery regulation and action of the major apoptotic nucleases dff40 cad and endonuclease g
    Journal of Cellular Biochemistry, 2005
    Co-Authors: Piotr Widlak, William T. Garrard
    Abstract:

    Toward the end of the 20th and beginning of the 21st centuries, clever in vitro biochemical complementation experiments and genetic screens from the laboratories of Xiaodong Wang, Shigekazu Nagata, and Ding Xue led to the discovery of two major apoptotic nucleases, termed DNA fragmentation factor (DFF) or caspase-activated DNase (CAD) and endonuclease G (Endo G). Both endonucleases attack chromatin to yield 3′-hydroxyl groups and 5′-phosphate residues, first at the level of 50–300 kb cleavage products and next at the level of internucleosomal DNA fragmentation, but these nucleases possess completely different cellular locations in normal cells and are regulated in vastly different ways. In non-apoptotic cells, DFF exists in the nucleus as a heterodimer, composed of a 45 kD chaperone and inhibitor subunit (DFF45) [also called inhibitor of CAD (ICAD-L)] and a 40 kD latent nuclease subunit (DFF40/CAD). Apoptotic Activation of caspase-3 or -7 results in the cleavage of DFF45/ICAD and release of active DFF40/CAD nuclease. DFF40's nuclease activity is further activated by specific chromosomal proteins, such as histone H1, HMGB1/2, and topoisomerase II. DFF is regulated by multiple pre- and post-Activation fail-safe steps, which include the requirements for DFF45/ICAD, Hsp70, and Hsp40 proteins to mediate appropriate folding during translation to generate a potentially activatable nuclease, and the synthesis in stoichiometric excess of the inhibitors (DFF45/35; ICAD-S/L). By contrast, Endo G resides in the mitochondrial intermembrane space in normal cells, and is released into the nucleus upon apoptotic disruption of mitochondrial membrane permeability in association with co-activators such as apoptosis-inducing factor (AIF). Understanding further regulatory check-points involved in safeguarding non-apoptotic cells against Accidental Activation of these nucleases remain as future challenges, as well as designing ways to selectively activate these nucleases in tumor cells. © 2005 Wiley-Liss, Inc.

  • Subunit Structures and Stoichiometries of Human DNA Fragmentation Factor Proteins before and after Induction of Apoptosis
    The Journal of biological chemistry, 2003
    Co-Authors: Piotr Widlak, Joanna Lanuszewska, Robert B. Cary, William T. Garrard
    Abstract:

    DNA fragmentation factor (DFF) is one of the major endonucleases responsible for internucleosomal DNA cleavage during apoptosis. Understanding the regulatory checkpoints involved in safeguarding non-apoptotic cells against Accidental Activation of this nuclease is as important as elucidating its Activation mechanisms during apoptosis. Here we address these issues by determining DFF native subunit structures and stoichiometries in human cells before and after induction of apoptosis using the technique of native pore-exclusion limit electrophoresis in combination with Western analyses. For comparison, we employed similar techniques with recombinant proteins in conjunction with atomic force microscopy. Before induction of apoptosis, the expression of DFF subunits varied widely among the cell types studied, and the chaperone/inhibitor subunits DFF45 and DFF35 unexpectedly existed primarily as monomers in vast excess of the latent nuclease subunit, DFF40, which was stoichiometrically associated with DFF45 to form heterodimers. DFF35 was exclusively cytoplasmic as a monomer. Nuclease Activation upon caspase-3 cleavage of DFF45/DFF35 was accompanied by DFF40 homo-oligomer formation, with a tetramer being the smallest unit. Interestingly, intact DFF45 can inhibit nuclease activity by associating with these homo-oligomers without mediating their disassembly. We conclude that DFF nuclease is regulated by multiple pre- and post-Activation fail-safe steps.

Piotr Widlak - One of the best experts on this subject based on the ideXlab platform.

  • Discovery, regulation, and action of the major apoptotic nucleases DFF40/CAD and endonuclease G.
    Journal of cellular biochemistry, 2005
    Co-Authors: Piotr Widlak, William T. Garrard
    Abstract:

    Toward the end of the 20th and beginning of the 21st centuries, clever in vitro biochemical complementation experiments and genetic screens from the laboratories of Xiaodong Wang, Shigekazu Nagata, and Ding Xue led to the discovery of two major apoptotic nucleases, termed DNA fragmentation factor (DFF) or caspase-activated DNase (CAD) and endonuclease G (Endo G). Both endonucleases attack chromatin to yield 3′-hydroxyl groups and 5′-phosphate residues, first at the level of 50–300 kb cleavage products and next at the level of internucleosomal DNA fragmentation, but these nucleases possess completely different cellular locations in normal cells and are regulated in vastly different ways. In non-apoptotic cells, DFF exists in the nucleus as a heterodimer, composed of a 45 kD chaperone and inhibitor subunit (DFF45) [also called inhibitor of CAD (ICAD-L)] and a 40 kD latent nuclease subunit (DFF40/CAD). Apoptotic Activation of caspase-3 or -7 results in the cleavage of DFF45/ICAD and release of active DFF40/CAD nuclease. DFF40's nuclease activity is further activated by specific chromosomal proteins, such as histone H1, HMGB1/2, and topoisomerase II. DFF is regulated by multiple pre- and post-Activation fail-safe steps, which include the requirements for DFF45/ICAD, Hsp70, and Hsp40 proteins to mediate appropriate folding during translation to generate a potentially activatable nuclease, and the synthesis in stoichiometric excess of the inhibitors (DFF45/35; ICAD-S/L). By contrast, Endo G resides in the mitochondrial intermembrane space in normal cells, and is released into the nucleus upon apoptotic disruption of mitochondrial membrane permeability in association with co-activators such as apoptosis-inducing factor (AIF). Understanding further regulatory check-points involved in safeguarding non-apoptotic cells against Accidental Activation of these nucleases remain as future challenges, as well as designing ways to selectively activate these nucleases in tumor cells. © 2005 Wiley-Liss, Inc.

  • discovery regulation and action of the major apoptotic nucleases dff40 cad and endonuclease g
    Journal of Cellular Biochemistry, 2005
    Co-Authors: Piotr Widlak, William T. Garrard
    Abstract:

    Toward the end of the 20th and beginning of the 21st centuries, clever in vitro biochemical complementation experiments and genetic screens from the laboratories of Xiaodong Wang, Shigekazu Nagata, and Ding Xue led to the discovery of two major apoptotic nucleases, termed DNA fragmentation factor (DFF) or caspase-activated DNase (CAD) and endonuclease G (Endo G). Both endonucleases attack chromatin to yield 3′-hydroxyl groups and 5′-phosphate residues, first at the level of 50–300 kb cleavage products and next at the level of internucleosomal DNA fragmentation, but these nucleases possess completely different cellular locations in normal cells and are regulated in vastly different ways. In non-apoptotic cells, DFF exists in the nucleus as a heterodimer, composed of a 45 kD chaperone and inhibitor subunit (DFF45) [also called inhibitor of CAD (ICAD-L)] and a 40 kD latent nuclease subunit (DFF40/CAD). Apoptotic Activation of caspase-3 or -7 results in the cleavage of DFF45/ICAD and release of active DFF40/CAD nuclease. DFF40's nuclease activity is further activated by specific chromosomal proteins, such as histone H1, HMGB1/2, and topoisomerase II. DFF is regulated by multiple pre- and post-Activation fail-safe steps, which include the requirements for DFF45/ICAD, Hsp70, and Hsp40 proteins to mediate appropriate folding during translation to generate a potentially activatable nuclease, and the synthesis in stoichiometric excess of the inhibitors (DFF45/35; ICAD-S/L). By contrast, Endo G resides in the mitochondrial intermembrane space in normal cells, and is released into the nucleus upon apoptotic disruption of mitochondrial membrane permeability in association with co-activators such as apoptosis-inducing factor (AIF). Understanding further regulatory check-points involved in safeguarding non-apoptotic cells against Accidental Activation of these nucleases remain as future challenges, as well as designing ways to selectively activate these nucleases in tumor cells. © 2005 Wiley-Liss, Inc.

  • Subunit Structures and Stoichiometries of Human DNA Fragmentation Factor Proteins before and after Induction of Apoptosis
    The Journal of biological chemistry, 2003
    Co-Authors: Piotr Widlak, Joanna Lanuszewska, Robert B. Cary, William T. Garrard
    Abstract:

    DNA fragmentation factor (DFF) is one of the major endonucleases responsible for internucleosomal DNA cleavage during apoptosis. Understanding the regulatory checkpoints involved in safeguarding non-apoptotic cells against Accidental Activation of this nuclease is as important as elucidating its Activation mechanisms during apoptosis. Here we address these issues by determining DFF native subunit structures and stoichiometries in human cells before and after induction of apoptosis using the technique of native pore-exclusion limit electrophoresis in combination with Western analyses. For comparison, we employed similar techniques with recombinant proteins in conjunction with atomic force microscopy. Before induction of apoptosis, the expression of DFF subunits varied widely among the cell types studied, and the chaperone/inhibitor subunits DFF45 and DFF35 unexpectedly existed primarily as monomers in vast excess of the latent nuclease subunit, DFF40, which was stoichiometrically associated with DFF45 to form heterodimers. DFF35 was exclusively cytoplasmic as a monomer. Nuclease Activation upon caspase-3 cleavage of DFF45/DFF35 was accompanied by DFF40 homo-oligomer formation, with a tetramer being the smallest unit. Interestingly, intact DFF45 can inhibit nuclease activity by associating with these homo-oligomers without mediating their disassembly. We conclude that DFF nuclease is regulated by multiple pre- and post-Activation fail-safe steps.

Toshiyuki Shimizu - One of the best experts on this subject based on the ideXlab platform.

  • Structural insights into ligand recognition and regulation of nucleic acid-sensing Toll-like receptors
    Current opinion in structural biology, 2017
    Co-Authors: Toshiyuki Shimizu
    Abstract:

    Toll-like receptors (TLRs) activate the innate immune system in response to invading pathogens. Although nucleic acids are one of the principal TLR ligands, they are not inherently pathogen-specific and, thus, carry the risk of triggering autoimmunity. There are multiple unique regulatory mechanisms aimed at preventing Accidental Activation of nucleic acid-sensing TLRs. Recent structural studies revealed that different nucleic acid-sensing TLRs have specific modes of recognizing nucleic acids as ligands regulated by diverse regulation mechanism both at the receptor and ligand levels. This review summarizes structural knowledge on the ligand recognition and regulation mechanism by nucleic acid-sensing TLRs.

Eicke Latz - One of the best experts on this subject based on the ideXlab platform.

  • Nucleic acid-sensing TLRs and autoimmunity: novel insights from structural and cell biology.
    Immunological reviews, 2015
    Co-Authors: Karin Pelka, Takuma Shibata, Kensuke Miyake, Eicke Latz
    Abstract:

    Invasion of pathogenic microorganisms or tissue damage activates innate immune signaling receptors that sample subcellular locations for foreign molecular structures, altered host molecules, or signs of compartment breaches. Upon engagement of innate immune receptors an acute but transient inflammatory response is initiated, aimed at the clearance of pathogens and cellular debris. Among the molecules that are sensed are nucleic acids, which activate several members of the transmembrane Toll-like receptor (TLR) family. Inappropriate recognition of nucleic acids by TLRs can cause inflammatory pathologies and autoimmunity. Here, we review the mechanisms involved in triggering nucleic acid-sensing TLRs and indicate checkpoints that restrict their Activation to endolysosomal compartments. These mechanisms are crucial to sample the content of endosomes for nucleic acids in the context of infection or tissue damage, yet prevent Accidental Activation by host nucleic acids under physiological conditions. Decoding the molecular mechanisms that regulate nucleic acid recognition by TLRs is central to understand pathologies linked to unrestricted nucleic acid sensing and to develop novel therapeutic strategies.

James A. Finch - One of the best experts on this subject based on the ideXlab platform.

  • Action of DETA, dextrin and carbonate on lead-contaminated sphalerite
    Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2004
    Co-Authors: Fereshteh Rashchi, James A. Finch, C. Sui
    Abstract:

    Lead ions can adsorb on sphalerite and promote flotation in the presence of xanthate. This process, known as Accidental Activation, is generally undesirable. One method of control is addition of a reagent to depress the lead ion effect. Three reagents, diethylenetriamine (DETA), dextrin, and sodium carbonate, were compared by measuring zeta potential and xanthate adsorption. The order of effectiveness in suppressing xanthate uptake over the conditions tested is dextrin > carbonate > DETA. The depressant action was attributed to a blocking mechanism through formation of surface complexes.

  • Sphalerite Activation and surface Pb ion concentration
    International Journal of Mineral Processing, 2002
    Co-Authors: Fereshteh Rashchi, C. Sui, James A. Finch
    Abstract:

    Abstract Activation of sphalerite by lead in the presence of ethyl xanthate was investigated by microflotation, EDTA extraction, and X-ray photoelectron spectroscopy (XPS). Activation was significant below pH 7 and declined to zero at pH 11. Interactions in the sphalerite/lead/xanthate system to account for the response are proposed. Flotation as a function of surface concentration of Pb, [Pb]surf (mg/cm2), showed a unique response regardless of source of lead (from solution or contact with galena).The [Pb]surf is linked to a Pb ion production model to try to estimate the grade of galena with the potential to cause Accidental Activation.

  • Quantifying Accidental Activation. Part I. Cu ion production
    Minerals Engineering, 2002
    Co-Authors: D. Lascelles, James A. Finch
    Abstract:

    Accidental Activation is a function of metal ion production, transfer and resultant flotation response. In Part I copper ion production from chalcocite and chalcopyrite was determined for single minerals and ores as a function of particle size using an EDTA extraction method. Copper ion production was inversely proportional to particle size. For single minerals, chalcocite produced about 50 times more Cu than chalcopyrite. The chalcopyrite-bearing ores gave higher copper ion production than for mineral alone, ascribed to galvanic interaction. A model was derived to predict surface concentration of Cu. The Cu production is compared to the resultant flotation effect in Part II.

  • Quantifying Accidental Activation. Part II. Cu Activation of pyrite
    Minerals Engineering, 2002
    Co-Authors: G Wong, D. Lascelles, James A. Finch
    Abstract:

    Abstract As a case study to quantify the flotation response, Cu Activation of pyrite was examined. Two particle sizes, 106/150 and 37/74 μm (surface area 304 and 901 cm 2 /g), were used. Micro-flotation was performed to determine the rate constant, k , as a function of surface concentration of copper, [Cu] surf . The [Cu] surf was determined by EDTA extraction and controlled by contact with Cu salt solution or with chalcopyrite and chalcocite particles. The rate constant relative to zero copper, k Cu / k 0 , followed the same trend against [Cu] surf for both particle sizes. Chalcocite gave a surface concentration about 40 times higher than chalcopyrite, corresponding to their relative ion production (the b -values in Part I). An estimate of mineral grade likely to cause Activation was made assuming the grade was inversely dependent on b and taking the critical grade of chalcocite as 0.1% ( Petruk, 2000 ). This gave a critical chalcopyrite grade of ca. 2%.