The Experts below are selected from a list of 174537 Experts worldwide ranked by ideXlab platform

James C. Paton - One of the best experts on this subject based on the ideXlab platform.

  • AB5 Subtilase Cytotoxin Inactivates the Endoplasmic reticulum Chaperone BiP
    Nature, 2006
    Co-Authors: Adrienne W. Paton, Travis Clarke Beddoe, Cheleste M. Thorpe, James C. Whisstock, Matthew C. J. Wilce, Jamie Rossjohn, Ursula M. Talbot, James C. Paton
    Abstract:

    AB5 toxins are produced by pathogenic bacteria and consist of enzymatic A subunits that corrupt essential eukaryotic cell functions, and pentameric B subunits that mediate uptake into the target cell. AB5 toxins include the Shiga, cholera and pertussis toxins and a recently discovered fourth family, subtilase cytotoxin, which is produced by certain Shiga toxigenic strains of Escherichia coli. Here we show that the extreme cytotoxicity of this toxin for eukaryotic cells is due to a specific single-site cleavage of the essential Endoplasmic reticulum chaperone BiP/GRP78. The A subunit is a subtilase-like serine protease; structural studies revealed an unusually deep active-site cleft, which accounts for its exquisite substrate specificity. A single amino-acid substitution in the BiP target site prevented cleavage, and co-expression of this resistant protein protected transfected cells against the toxin. BiP is a master regulator of Endoplasmic reticulum function, and its cleavage by subtilase cytotoxin represents a previously unknown trigger for cell death. Shiga toxigenic Escherichia coli can cause gastrointestinal disease in humans, with potentially life-threatening consequences. This paper elucidates the mechanism of the bacteria-induced host cell death; a protein crucially involved in Endoplasmic reticulum function is specifically targeted and inactivated by the toxin's protease subunit.

  • AB_5 subtilase cytotoxin inactivates the Endoplasmic reticulum chaperone BiP
    Nature, 2006
    Co-Authors: Adrienne W. Paton, Travis Clarke Beddoe, Cheleste M. Thorpe, James C. Whisstock, Matthew C. J. Wilce, Jamie Rossjohn, Ursula M. Talbot, James C. Paton
    Abstract:

    AB_5 toxins are produced by pathogenic bacteria and consist of enzymatic A subunits that corrupt essential eukaryotic cell functions, and pentameric B subunits that mediate uptake into the target cell. AB_5 toxins include the Shiga, cholera and pertussis toxins and a recently discovered fourth family, subtilase cytotoxin, which is produced by certain Shiga toxigenic strains of Escherichia coli . Here we show that the extreme cytotoxicity of this toxin for eukaryotic cells is due to a specific single-site cleavage of the essential Endoplasmic reticulum chaperone BiP/GRP78. The A subunit is a subtilase-like serine protease; structural studies revealed an unusually deep active-site cleft, which accounts for its exquisite substrate specificity. A single amino-acid substitution in the BiP target site prevented cleavage, and co-expression of this resistant protein protected transfected cells against the toxin. BiP is a master regulator of Endoplasmic reticulum function, and its cleavage by subtilase cytotoxin represents a previously unknown trigger for cell death. Shiga toxigenic Escherichia coli can cause gastrointestinal disease in humans, with potentially life-threatening consequences. This paper elucidates the mechanism of the bacteria-induced host cell death; a protein crucially involved in Endoplasmic reticulum function is specifically targeted and inactivated by the toxin's protease subunit.

Laurie H Glimcher - One of the best experts on this subject based on the ideXlab platform.

  • the Endoplasmic reticulum stress response in immunity and autoimmunity
    Nature Reviews Immunology, 2008
    Co-Authors: Derrick J Todd, Laurie H Glimcher
    Abstract:

    The unfolded-protein response (UPR) protects cells from stress induced by the accumulation of unfolded proteins in the Endoplasmic reticulum. As discussed here, an important role for the UPR has recently been described in the immune system, dysregulation of which could potentially contribute to autoimmunity. Many exogenous sources of stress can lead to cell death. In recent years, endogenous cellular sources of stress have also been identified, including the stress that arises from the accumulation of unfolded proteins within a cell's Endoplasmic reticulum (ER). To counterbalance this type of ER stress, higher eukaryotic cells possess a three-pronged signal-transduction pathway termed the unfolded-protein response (UPR). This Review focuses on the role of the UPR in the mammalian immune system and how manipulation of this complex signalling pathway may be of therapeutic benefit in human disease.

Randal J Kaufma - One of the best experts on this subject based on the ideXlab platform.

  • protein misfolding in the Endoplasmic reticulum as a conduit to human disease
    Nature, 2016
    Co-Authors: Miao Wang, Randal J Kaufma
    Abstract:

    In eukaryotic cells, the Endoplasmic reticulum is essential for the folding and trafficking of proteins that enter the secretory pathway. Environmental insults or increased protein synthesis often lead to protein misfolding in the organelle, the accumulation of misfolded or unfolded proteins - known as Endoplasmic reticulum stress - and the activation of the adaptive unfolded protein response to restore homeostasis. If protein misfolding is not resolved, cells die. Endoplasmic reticulum stress and activation of the unfolded protein response help to determine cell fate and function. Furthermore, Endoplasmic reticulum stress contributes to the aetiology of many human diseases.

  • from Endoplasmic reticulum stress to the inflammatory response
    Nature, 2008
    Co-Authors: Kezhong Zhang, Randal J Kaufma
    Abstract:

    The Endoplasmic reticulum is responsible for much of a cell's protein synthesis and folding, but it also has an important role in sensing cellular stress. Recently, it has been shown that the Endoplasmic reticulum mediates a specific set of intracellular signalling pathways in response to the accumulation of unfolded or misfolded proteins, and these pathways are collectively known as the unfolded-protein response. New observations suggest that the unfolded-protein response can initiate inflammation, and the coupling of these responses in specialized cells and tissues is now thought to be fundamental in the pathogenesis of inflammatory diseases. The knowledge gained from this emerging field will aid in the development of therapies for modulating cellular stress and inflammation.

Peter Walter - One of the best experts on this subject based on the ideXlab platform.

Adrienne W. Paton - One of the best experts on this subject based on the ideXlab platform.

  • AB5 Subtilase Cytotoxin Inactivates the Endoplasmic reticulum Chaperone BiP
    Nature, 2006
    Co-Authors: Adrienne W. Paton, Travis Clarke Beddoe, Cheleste M. Thorpe, James C. Whisstock, Matthew C. J. Wilce, Jamie Rossjohn, Ursula M. Talbot, James C. Paton
    Abstract:

    AB5 toxins are produced by pathogenic bacteria and consist of enzymatic A subunits that corrupt essential eukaryotic cell functions, and pentameric B subunits that mediate uptake into the target cell. AB5 toxins include the Shiga, cholera and pertussis toxins and a recently discovered fourth family, subtilase cytotoxin, which is produced by certain Shiga toxigenic strains of Escherichia coli. Here we show that the extreme cytotoxicity of this toxin for eukaryotic cells is due to a specific single-site cleavage of the essential Endoplasmic reticulum chaperone BiP/GRP78. The A subunit is a subtilase-like serine protease; structural studies revealed an unusually deep active-site cleft, which accounts for its exquisite substrate specificity. A single amino-acid substitution in the BiP target site prevented cleavage, and co-expression of this resistant protein protected transfected cells against the toxin. BiP is a master regulator of Endoplasmic reticulum function, and its cleavage by subtilase cytotoxin represents a previously unknown trigger for cell death. Shiga toxigenic Escherichia coli can cause gastrointestinal disease in humans, with potentially life-threatening consequences. This paper elucidates the mechanism of the bacteria-induced host cell death; a protein crucially involved in Endoplasmic reticulum function is specifically targeted and inactivated by the toxin's protease subunit.

  • AB_5 subtilase cytotoxin inactivates the Endoplasmic reticulum chaperone BiP
    Nature, 2006
    Co-Authors: Adrienne W. Paton, Travis Clarke Beddoe, Cheleste M. Thorpe, James C. Whisstock, Matthew C. J. Wilce, Jamie Rossjohn, Ursula M. Talbot, James C. Paton
    Abstract:

    AB_5 toxins are produced by pathogenic bacteria and consist of enzymatic A subunits that corrupt essential eukaryotic cell functions, and pentameric B subunits that mediate uptake into the target cell. AB_5 toxins include the Shiga, cholera and pertussis toxins and a recently discovered fourth family, subtilase cytotoxin, which is produced by certain Shiga toxigenic strains of Escherichia coli . Here we show that the extreme cytotoxicity of this toxin for eukaryotic cells is due to a specific single-site cleavage of the essential Endoplasmic reticulum chaperone BiP/GRP78. The A subunit is a subtilase-like serine protease; structural studies revealed an unusually deep active-site cleft, which accounts for its exquisite substrate specificity. A single amino-acid substitution in the BiP target site prevented cleavage, and co-expression of this resistant protein protected transfected cells against the toxin. BiP is a master regulator of Endoplasmic reticulum function, and its cleavage by subtilase cytotoxin represents a previously unknown trigger for cell death. Shiga toxigenic Escherichia coli can cause gastrointestinal disease in humans, with potentially life-threatening consequences. This paper elucidates the mechanism of the bacteria-induced host cell death; a protein crucially involved in Endoplasmic reticulum function is specifically targeted and inactivated by the toxin's protease subunit.