Browse
Submit Data
Databases
API
Help

Dataset Information

23 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Granulysin: killer lymphocyte safeguard against microbes.

ABSTRACT: Primary T cell immunodeficiency and HIV-infected patients are plagued by non-viral infections caused by bacteria, fungi, and parasites, suggesting an important and underappreciated role for T lymphocytes in controlling microbes. Here, we review recent studies showing that killer lymphocytes use the antimicrobial cytotoxic granule pore-forming peptide granulysin, induced by microbial exposure, to permeabilize cholesterol-poor microbial membranes and deliver death-inducing granzymes into these pathogens. Granulysin and granzymes cause microptosis, programmed cell death in microbes, by inducing reactive oxygen species and destroying microbial antioxidant defenses and disrupting biosynthetic and central metabolism pathways required for their survival, including protein synthesis, glycolysis, and the Krebs cycle.

SUBMITTER: Dotiwala F

PROVIDER: S-EPMC6800608 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Granulysin: killer lymphocyte safeguard against microbes.

Dotiwala Farokh F Lieberman Judy J

Current opinion in immunology 20190518

Primary T cell immunodeficiency and HIV-infected patients are plagued by non-viral infections caused by bacteria, fungi, and parasites, suggesting an important and underappreciated role for T lymphocytes in controlling microbes. Here, we review recent studies showing that killer lymphocytes use the antimicrobial cytotoxic granule pore-forming peptide granulysin, induced by microbial exposure, to permeabilize cholesterol-poor microbial membranes and deliver death-inducing granzymes into these pat ...[more]

PMID: 31112765

Similar Datasets

Killer lymphocytes use granulysin, perforin and granzymes to kill intracellular parasites.

Project description:Protozoan infections are a serious global health problem. Natural killer (NK) cells and cytolytic T lymphocytes (CTLs) eliminate pathogen-infected cells by releasing cytolytic granule contents--granzyme (Gzm) proteases and the pore-forming perforin (PFN)--into the infected cell. However, these cytotoxic molecules do not kill intracellular parasites. CD8(+) CTLs protect against parasite infections in mice primarily by secreting interferon (IFN)-?. However, human, but not rodent, cytotoxic granules contain the antimicrobial peptide granulysin (GNLY), which selectively destroys cholesterol-poor microbial membranes, and GNLY, PFN and Gzms rapidly kill intracellular bacteria. Here we show that GNLY delivers Gzms into three protozoan parasites (Trypanosoma cruzi, Toxoplasma gondii and Leishmania major), in which the Gzms generate superoxide and inactivate oxidative defense enzymes to kill the parasite. PFN delivers GNLY and Gzms into infected cells, and GNLY then delivers Gzms to the intracellular parasites. Killer cell-mediated parasite death, which we term 'microbe-programmed cell death' or 'microptosis', is caspase independent but resembles mammalian apoptosis, causing mitochondrial swelling, transmembrane potential dissipation, membrane blebbing, phosphatidylserine exposure, DNA damage and chromatin condensation. GNLY-transgenic mice are protected against infection by T. cruzi and T. gondii, and survive infections that are lethal to wild-type mice. Thus, GNLY-, PFN- and Gzm-mediated elimination of intracellular protozoan parasites is an unappreciated immune defense mechanism.

| S-EPMC7325279 | biostudies-literature

ATM and KAT5 safeguard replicating chromatin against formaldehyde damage.

Project description:Many carcinogens damage both DNA and protein constituents of chromatin, and it is unclear how cells respond to this compound injury. We examined activation of the main DNA damage-responsive kinase ATM and formation of DNA double-strand breaks (DSB) by formaldehyde (FA) that forms histone adducts and replication-blocking DNA-protein crosslinks (DPC). We found that low FA doses caused a strong and rapid activation of ATM signaling in human cells, which was ATR-independent and restricted to S-phase. High FA doses inactivated ATM via its covalent dimerization and formation of larger crosslinks. FA-induced ATM signaling showed higher CHK2 phosphorylation but much lower phospho-KAP1 relative to DSB inducers. Replication blockage by DPC did not produce damaged forks or detectable amounts of DSB during the main wave of ATM activation, which did not require MRE11. Chromatin-monitoring KAT5 (Tip60) acetyltransferase was responsible for acetylation and activation of ATM by FA. KAT5 and ATM were equally important for triggering of intra-S-phase checkpoint and ATM signaling promoted recovery of normal human cells after low-dose FA. Our results revealed a major role of the KAT5-ATM axis in protection of replicating chromatin against damage by the endogenous carcinogen FA.

| S-EPMC4705693 | biostudies-literature

Logical modeling of thymus and natural killer lymphocyte differentiation.

Project description:Thymus (T) and natural killer (NK) lymphocytes are important barriers against diseases. Therefore, it is necessary to understand regulatory mechanisms related to the cell fate decisions involved in the production of these cells. Although some individual information related to T and NK lymphocyte cell fate decisions have been revealed, the related network and its dynamical characteristics still have not been well understood. By integrating individual information and comparing with experimental data, we construct a comprehensive regulatory network and a logical model related to T and NK lymphocyte differentiation. We aim to explore possible mechanisms of how each lineage differentiation is realized by systematically screening individual perturbations. When determining the perturbation strategies, the state transition can be used to identify the roles of specific genes in cell type selection and reprogramming. In agreement with experimental observations, the dynamics of the model correctly restates the cell differentiation processes from common lymphoid progenitors to CD4+ T cells, CD8+ T cells, and NK cells. Our analysis reveals that some specific perturbations can give rise to directional cell differentiation or reprogramming. We test our in silico results by using known experimental observations. The integrated network and the logical model presented here might be a good candidate for providing qualitative mechanisms of cell fate specification involved in T and NK lymphocyte cell fate decisions.

| S-EPMC7981374 | biostudies-literature

Intestinal microbes affect phenotypes and functions of invariant natural killer T cells in mice.

Project description:Invariant natural killer T (iNKT) cells undergo canonical, V?14-J?18 rearrangement of the T-cell receptor (TCR) in mice; this form of the TCR recognizes glycolipids presented by CD1d. iNKT cells mediate many different immune reactions. Their constitutive activated and memory phenotype and rapid initiation of effector functions after stimulation indicate previous antigen-specific stimulation. However, little is known about this process. We investigated whether symbiotic microbes can determine the activated phenotype and function of iNKT cells.We analyzed the numbers, phenotypes, and functions of iNKT cells in germ-free mice, germ-free mice reconstituted with specified bacteria, and mice housed in specific pathogen-free environments.Specific pathogen-free mice, obtained from different vendors, have different intestinal microbiota. iNKT cells isolated from these mice differed in TCR V?7 frequency and cytokine response to antigen, which depended on the environment. iNKT cells isolated from germ-free mice had a less mature phenotype and were hyporesponsive to activation with the antigen ?-galactosylceramide. Intragastric exposure of germ-free mice to Sphingomonas bacteria, which carry iNKT cell antigens, fully established phenotypic maturity of iNKT cells. In contrast, reconstitution with Escherichia coli, which lack specific antigens for iNKT cells, did not affect the phenotype of iNKT cells. The effects of intestinal microbes on iNKT cell responsiveness did not require Toll-like receptor signals, which can activate iNKT cells independently of TCR stimulation.Intestinal microbes can affect iNKT cell phenotypes and functions in mice.

| S-EPMC3404247 | biostudies-other

Rif1 promotes a repressive chromatin state to safeguard against endogenous retrovirus activation.

Project description:Transposable elements, including endogenous retroviruses (ERVs), constitute a large fraction of the mammalian genome. They are transcriptionally silenced during early development to protect genome integrity and aberrant transcription. However, the mechanisms that control their repression are not fully understood. To systematically study ERV repression, we carried out an RNAi screen in mouse embryonic stem cells (ESCs) and identified a list of novel regulators. Among them, Rif1 displays the strongest effect. Rif1 depletion by RNAi or gene deletion led to increased transcription and increased chromatin accessibility at ERV regions and their neighboring genes. This transcriptional de-repression becomes more severe when DNA methylation is lost. On the mechanistic level, Rif1 directly occupies ERVs and is required for repressive histone mark H3K9me3 and H3K27me3 assembly and DNA methylation. It interacts with histone methyltransferases and facilitates their recruitment to ERV regions. Importantly, Rif1 represses ERVs in human ESCs as well, and the evolutionally-conserved HEAT-like domain is essential for its function. Finally, Rif1 acts as a barrier during somatic cell reprogramming, and its depletion significantly enhances reprogramming efficiency. Together, our study uncovered many previously uncharacterized repressors of ERVs, and defined an essential role of Rif1 in the epigenetic defense against ERV activation.

| S-EPMC5727408 | biostudies-literature

In vivo HIV-1 nuclear condensates safeguard against cGAS and license reverse transcription

Project description:Entry of viral capsids into the nucleus induces the formation of biomolecular condensates called HIV-1 membraneless organelles (HIV-1-MLOs). Several questions remain about their persistence, in vivo formation, composition, and function. Our study reveals that HIV-1-MLOs persisted for several weeks in infected cells, and their abundance correlated with viral infectivity. Using an appropriate animal model, we show that HIV-1-MLOs were formed in vivo during acute infection. To explore the viral structures present within these biomolecular condensates, we used a combination of double immunogold labeling, electron microscopy and tomography, and unveiled a diverse array of viral core structures. Our functional analyses showed that HIV-1-MLOs remained stable during treatment with a reverse transcriptase inhibitor, maintaining the virus in a dormant state. Drug withdrawal restored reverse transcription, promoting efficient virus replication akin to that observed in latently infected patients on antiretroviral therapy. However, when HIV-1 MLOs were deliberately disassembled by pharmacological treatment, we observed a complete loss of viral infectivity. Our findings show that HIV-1 MLOs shield the final reverse transcription product from host immune detection.

| S-SCDT-10_1038-S44318-024-00316-W | biostudies-other

Alternative splicing of <i>GSDMB</i> modulates killer lymphocyte-triggered pyroptosis.

Project description:Granzyme A from killer lymphocytes cleaves gasdermin B (GSDMB) and triggers pyroptosis in targeted human tumor cells, eliciting antitumor immunity. However, GSDMB has a controversial role in pyroptosis and has been linked to both anti- and protumor functions. Here, we found that GSDMB splicing variants are functionally distinct. Cleaved N-terminal (NT) fragments of GSDMB isoforms 3 and 4 caused pyroptosis, but isoforms 1, 2, and 5 did not. The nonfunctional isoforms have a deleted or modified exon 6 and therefore lack a stable belt motif. The belt likely contributes to the insertion of oligomeric GSDMB-NTs into the membrane. Consistently, noncytotoxic GSDMB-NTs blocked pyroptosis caused by cytotoxic GSDMB-NTs in a dominant-negative manner. Upon natural killer (NK) cell attack, GSDMB3-expressing cells died by pyroptosis, whereas GSDMB4-expressing cells died by mixed pyroptosis and apoptosis, and GSDMB1/2-expressing cells died only by apoptosis. GSDMB4 partially resisted NK cell-triggered cleavage, suggesting that only GSDMB3 is fully functional. GSDMB1-3 were the most abundant isoforms in the tested tumor cell lines and were similarly induced by interferon-γ and the chemotherapy drug methotrexate. Expression of cytotoxic GSDMB3/4 isoforms, but not GSDMB1/2 isoforms that are frequently up-regulated in tumors, was associated with better outcomes in bladder and cervical cancers, suggesting that GSDMB3/4-mediated pyroptosis was protective in those tumors. Our study indicates that tumors may block and evade killer cell-triggered pyroptosis by generating noncytotoxic GSDMB isoforms. Therefore, therapeutics that favor the production of cytotoxic GSDMB isoforms by alternative splicing may improve antitumor immunity.

| S-EPMC10338320 | biostudies-literature

Pax3 and Pax7 play essential safeguard functions against environmental stress-induced birth defects

Project description:Exposure to environmental teratogenic pollutant leads to severe birth defects. However, the biological events underlying these developmental abnormalities remain undefined. Here we report a molecular link between an environmental stress response pathway and key developmental genes during craniofacial development. In our study, we focused on the development of the facial prominences at E11.5. To do so, we compared the transcriptomes of mutant embryos (*Pax3Pax3-ERD/GFP *called DM in the microarray samples) to the one of control embryos (*Pax3GFP/+ *called GFP in the sample names). These are knock-in genetic models described in Bajard et al., 2006 and Relaix et al., 2005. In both of them a cassette coding for the GFP is replacing one allele of the Pax3 gene. The Pax3-ERD allele is a conditional one that drives the expression of the dominant negative form of Pax3 (Pax3-ERD) composed of the Pax3 DNA binding domain fused to the engrailed repressor domain (ERD) upon activation of a Cre recombinase. In this study, the Cre was driven by the zygote specific PGK enhancer. Strikingly, mutant mice with impaired Pax3/7 function display severe craniofacial defects. We show these are associated with an up-regulation of the signaling pathway mediated by the Aryl hydrocarbon Receptor (AhR), the receptor to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), revealing a genetic interaction between Pax3 and AhR signaling. Activation of AhR signaling in Pax3-deficient embryos drives facial mesenchymal cells out of the cell cycle through the up-regulation of p21 expression. Accordingly, inhibiting AhR activity rescues the cycling status of these cells and the facial closure of Pax3/7 mutants. Together, our findings demonstrate that the regulation of AhR signaling by Pax3/7 is required to protect against TCDD/AhR-mediated teratogenesis during craniofacial development.

2015-04-06 | E-MTAB-3238 | biostudies-arrayexpress

Peripheral Dopamine Controlled by Gut Microbes Inhibits Invariant Natural Killer T Cell-Mediated Hepatitis.

Project description:Neurotransmitters have been shown to regulate immune responses, and thereby are critically related to autoimmune diseases. Here we showed that depletion of dopaminergic neurons significantly promoted activation of hepatic iNKT cells and augmented concanavalin A (Con A)-induced liver injury. The suppressive effect of dopamine on iNKT cells was mediated by D1-like receptor-PKA pathway. Clearance of gut microbiota by antibiotic cocktail reduced synthesis of dopamine in intestines and exacerbated liver damage, and that could be restored by recovery of gut microbiota or replenishment of D1-like receptor agonist. Our results demonstrate that peripheral dopamine controlled by gut microbes inhibits IL4 and IFNγ production in iNKT cells and suppresses iNKT cell-mediated hepatitis. Together, we propose a gut microbe-nervous system-immune system regulatory axis in modulating autoimmune hepatitis.

| S-EPMC6199378 | biostudies-literature

A model for DNA replication showing how dormant origins safeguard against replication fork failure.

Project description:Replication origins are 'licensed' for a single initiation event before entry into S phase; however, many licensed replication origins are not used, but instead remain dormant. The use of these dormant origins helps cells to survive replication stresses that block replication fork movement. Here, we present a computer model of the replication of a typical metazoan origin cluster in which origins are assigned a certain initiation probability per unit time and are then activated stochastically during S phase. The output of this model is in good agreement with experimental data and shows how inefficient dormant origins can be activated when replication forks are inhibited. The model also shows how dormant origins can allow replication to complete even if some forks stall irreversibly. This provides a simple explanation for how replication origin firing is regulated, which simultaneously provides protection against replicative stress while minimizing the cost of using large numbers of replication forks.

| S-EPMC2644062 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data