Search results for "Toxic proteins"
showing 10 items of 19 documents
Global Functional Analyses of Cellular Responses to Pore-Forming Toxins
2011
Here we present the first global functional analysis of cellular responses to pore-forming toxins (PFTs). PFTs are uniquely important bacterial virulence factors, comprising the single largest class of bacterial protein toxins and being important for the pathogenesis in humans of many Gram positive and Gram negative bacteria. Their mode of action is deceptively simple, poking holes in the plasma membrane of cells. The scattered studies to date of PFT-host cell interactions indicate a handful of genes are involved in cellular defenses to PFTs. How many genes are involved in cellular defenses against PFTs and how cellular defenses are coordinated are unknown. To address these questions, we pe…
Toxic Proteins and Peptides
1994
Many animals produce poisonous substances which, even at a relatively low dose, are deleterious or lethal to other organisms, including man. They may serve on the one hand to disable or kill prey, or on the other hand as a protection or defence against predators. These substances are mostly produced by special glands, and both poison reservoirs and specialized structures for delivering the secretion, e.g. stings or modified mouthparts or fangs, are usually also present. In accordance with the aims of this book, we will deal with the comparative biochemistry of the animal toxins as natural products with special structures and functions; a discussion of the mechanisms of their pharmacological…
Cigarette smoke promotes inflammasome‐independent activation of caspase‐1 and ‐4 leading to gasdermin D cleavage in human macrophages
2022
Mechanisms and consequences of gasdermin D (GSDMD) activation in cigarette smoke (CS)-associated inflammation and lung disease are unknown. GSDMD is a downstream effector of caspase-1, -8, and -4. Upon cleavage, GSDMD generates pores into cell membranes. Different degrees of GSDMD activation are associated with a range of physiological outputs ranging from cell hyperactivation to pyroptosis. We have previously reported that in human monocyte-derived macrophages CS extract (CSE) inhibits the NLRP3 inflammasome and shifts the response to lipopolysaccharide (LPS) towards the TLR4-TRIF axis leading to activation of caspase-8, which, in turn, activates caspase-1. In the present work, we investig…
Pore formation by Vibrio cholerae cytolysin requires cholesterol in both monolayers of the target membrane
2007
Vibrio cholerae cytolysin (VCC) forms oligomeric transmembrane pores in cholesterol-rich membranes. To better understand this process, we used planar bilayer membranes. In symmetric membranes, the rate of the channel formation by VCC has a superlinear dependency on the cholesterol membrane fraction. Thus, more than one cholesterol molecule can facilitate VCC-pore formation. In asymmetric membranes, the rate of pore formation is limited by the leaflet with the lower cholesterol content. Methyl-beta-cyclodextrin, which removes cholesterol from membranes, rapidly inhibits VCC pore formation, even when it is added to the side opposite that of VCC addition. The results suggest that cholesterol i…
Perforin deficiency attenuates inflammation and tumor growth in colitis-associated cancer
2010
Background: Patients with inflammatory bowel disease (IBD) have a markedly increased risk to develop colon cancer, but there are only limited data about the host antitumor response in such colitis-associated cancer. In the present study we aimed at assessing the role of perforin-dependent effector mechanisms in the immune response in a murine model of colitis-associated colon cancer. Methods: Wildtype and perforin-deficient mice were analyzed in a mouse model of colitis-associated colon cancer using azoxymethane (AOM) and dextran sodium sulfate (DSS). Results: Tumors of wildtype mice showed infiltration of CD4+, CD8+ T cells, natural killer (NK) cells, high numbers of apoptotic cells, and e…
Blattella germanica displays a large arsenal of antimicrobial peptide genes
2020
Defence systems against microbial pathogens are present in most living beings. The German cockroach Blattella germanica requires these systems to adapt to unhealthy environments with abundance of pathogenic microbes, in addition to potentially control its symbiotic systems. To handle this situation, four antimicrobial gene families (defensins, termicins, drosomycins and attacins) were expanded in its genome. Remarkably, a new gene family (blattellicins) emerged recently after duplication and fast evolution of an attacin gene, which is now encoding larger proteins with the presence of a long stretch of glutamines and glutamic acids. Phylogenetic reconstruction, within Blattellinae, suggests …
An Ovalbumin Peptide-Specific Cytotoxic T Cell Clone with Antigen Self-Presentation Capacity Uses Two Distinct Mechanisms to Kill Target Cells
1993
Abstract Cloned 10BK.1 T cells with specificity for the ovalbumin peptide OVA257-264 are representative of a novel cell type within the CD8 + subset of T cells. In the presence and in the absence of added antigen presenting cells these T cells react toward antigen (Ag) by proliferation and lymphokine production. These data suggest self-presentation of the Ag by 10BK.1 cells. Here we present evidence that 10BK.1 cells exhibit cytotoxic activity that involves two different cytotoxic effector mechanisms. (i) One mechanism is fast killing activity, apparent within 4 hr. Constitutive mouse T cell-specific proteinase-1 (MTSP-1) activity, constitutive expression of MTSP-1 RNA, increased by Ag chal…
A lipocentric view of peptide-induced pores
2010
Although lipid membranes serve as effective sealing barriers for the passage of most polar solutes, nonmediated leakage is not completely improbable. A high activation energy normally keeps unassisted bilayer permeation at a very low frequency, but lipids are able to self-organize as pores even in peptide-free and protein-free membranes. The probability of leakage phenomena increases under conditions such as phase coexistence, external stress or perturbation associated to binding of nonlipidic molecules. Here, we argue that pore formation can be viewed as an intrinsic property of lipid bilayers, with strong similarities in the structure and mechanism between pores formed with participation …
Gamma delta T cells inhibit in vitro growth of the asexual blood stages of Plasmodium falciparum by a granule exocytosis-dependent cytotoxic pathway …
2004
Several reports have stated the ability of gamma delta T cells to inhibit the growth of the asexual blood stages of Plasmodium falciparum in vitro. However, little information is available about the mechanisms involved. In this study, in vitro systems were used to study the role of the granule exocytosis-dependent cytotoxic pathway in the growth inhibition/killing of P. falciparum by human gamma delta T cells. Our results show that the inhibition requires cell-to-cell contact and that gamma delta T cells kill the asexual blood stages of P. falciparum through a granule exocytosis-dependent cytotoxic pathway after recognition of certain ligands or molecules expressed on the surface of infecte…
Pore formation by Vibrio cholerae cytolysin follows the same archetypical mode as beta-barrel toxins from gram-positive organisms.
2009
Vibrio cholerae cytolysin (VCC) forms SDS-stable heptameric beta-barrel transmembrane pores in mammalian cell membranes. In contrast to structurally related pore formers of gram-positive organisms, no oligomeric prepore stage of assembly has been detected to date. In the present study, disulfide bonds were engineered to tie the pore-forming amino acid sequence to adjacent domains. In their nonreduced form, mutants were able to bind to rabbit erythrocytes and to native erythrocyte membranes suspended in PBS solution and form SDS-labile oligomers. These remained nonfunctional and represented the long-sought VCC prepores. Disulfide bond reduction in these oligomers released the pore-forming se…