Browse
Submit Data
Databases
API
Help

Dataset Information

18 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Coronin-1A links cytoskeleton dynamics to TCR alpha beta-induced cell signaling.

ABSTRACT: Actin polymerization plays a critical role in activated T lymphocytes both in regulating T cell receptor (TCR)-induced immunological synapse (IS) formation and signaling. Using gene targeting, we demonstrate that the hematopoietic specific, actin- and Arp2/3 complex-binding protein coronin-1A contributes to both processes. Coronin-1A-deficient mice specifically showed alterations in terminal development and the survival of alpha beta T cells, together with defects in cell activation and cytokine production following TCR triggering. The mutant T cells further displayed excessive accumulation yet reduced dynamics of F-actin and the WASP-Arp2/3 machinery at the IS, correlating with extended cell-cell contact. Cell signaling was also affected with the basal activation of the stress kinases sAPK/JNK1/2; and deficits in TCR-induced Ca2+ influx and phosphorylation and degradation of the inhibitor of NF-kappaB (I kappa B). Coronin-1A therefore links cytoskeleton plasticity with the functioning of discrete TCR signaling components. This function may be required to adjust TCR responses to selecting ligands accounting in part for the homeostasis defect that impacts alpha beta T cells in coronin-1A deficient mice, with the exclusion of other lympho/hematopoietic lineages.

SUBMITTER: Mugnier B

PROVIDER: S-EPMC2568942 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

How alpha beta T cells deal with induced TCR alpha ablation.

Project description:On deletion of the gene encoding the constant region of the T cell antigen receptor (TCR)alpha chain in mature T cells by induced Cre-mediated recombination, the cells lose most of their TCR from the cell surface within 7--10 days, but minute amounts of surface-bound TCR beta chains are retained for long periods of time. In a situation in which cellular influx from the thymus is blocked, TCR-deficient naive T cells decay over time, the decay rates being faster for CD8(+) cells (t(1/2) approximately 16 days) than for CD4(+) cells (t(1/2) approximately 46 days). TCR(+) naïve cells are either maintained (CD8(+)) or decay more slowly (CD4(+); t(1/2) approximately 78 days.) Numbers of TCR-deficient memory T cells decline very slowly (CD8(+) cells; t(1/2) approximately 52 days) or not at all (CD4(+) cells), but at the population level, these cells fail to expand as their TCR(+) counterparts do. Together with earlier data on T cell maintenance in environments lacking appropriate major histocompatibility complex antigens, these data argue against the possibility that spontaneous ligand-independent signaling by the alpha beta TCR contributes significantly to T-cell homeostasis.

| S-EPMC37506 | biostudies-literature

Mast cell function is not altered by Coronin-1A deficiency.

Project description:Coronin-1A is a WD repeat protein family member, highly expressed in all hematopoietic lineages, and acts as a regulator of F-actin dynamics and Ca2+ signaling. In Coro1a(Lmb3) mice results in inactivation of the protein and leads to disease resistance in a model of lupus erythematosus. In Coro1a(-/-) and Coro1a(Lmb3) mice, peripheral T cells exhibit impairments in survival, migration, activation, and Ca2+ flux. In this study, we show that in vitro-differentiated mast cells from Coro1a(Lmb3) mice are viable, developed normally, and are fully functional in assays of degranulation, cytokine secretion, and chemotactic migration, despite increased F-actin levels. In Coro1a(Lmb3) mast cells, Ca2+ flux in response to physiological Fc?RI stimulation is unaffected. Finally, Coro1a(Lmb3) mice showed similar in vivo mast cell responses as the WT mice. Coronin-1B and Coronin-1C expression levels were not increased in Coro1a(Lmb3) mast cells but were higher in mast cells than in CD4 T cells or B cells in WT mice. We conclude that Coronin-1A activity is not required for mast cell function.

| S-EPMC2974433 | biostudies-literature

Nonmuscle myosin IIB links cytoskeleton to IRE1? signaling during ER stress.

Project description:Here we identify and characterize a cytoskeletal myosin protein required for IRE1? oligomerization, activation, and signaling. Proteomic screening identified nonmuscle myosin heavy chain IIB (NMHCIIB), a subunit of nonmuscle myosin IIB (NMIIB), as an ER stress-dependent interacting protein specific to IRE1?. Loss of NMIIB compromises XBP1s and UPR target gene expression with no effect on the PERK pathway. Mechanistically, NMIIB is required for IRE1? aggregation and foci formation under ER stress. The NMIIB-mediated effect on IRE1? signaling is in part dependent on the phosphorylation of myosin regulatory light chain and the actomyosin contractility of NMIIB. Biologically, the function of NMIIB in ER stress response is conserved as both mammalian cells and C. elegans lacking NMIIB exhibit hypersensitivity to ER stress. Thus, optimal IRE1? activation and signaling require concerted coordination between the ER and cytoskeleton.

| S-EPMC3547290 | biostudies-literature

Identification of novel Coronin 1A interacting proteins

Project description:Severe combined immunodeficiency 8 (IMD8) is caused by mutations in the human Coronin 1A (Coro1A). The clinical presentation of IMD8 patients is characterized by recurrent bacterial infections, suggesting an important role of Coro1A in innate immunity. To analyze the molecular mechanism of Coro1A during neutrophil recruitment, we identified the Coro1A interactome by conducting co-immunoprecipitation (Co-IP) experiments using GFP NanoTrap technology and subsequent mass spectrometry (LC-MS/MS) using human neutrophil-like differentiated HL-60 (dHL-60) cells stably expressing Coro1A-EGFP (dHL-60-Coro1A-EGFP) cells.

2017-06-29 | PXD004635 | Pride

The disease-linked Glu-26-Lys mutant version of Coronin 1A exhibits pleiotropic and pathway-specific signaling defects.

Project description:Coronin 1A (Coro1A) is involved in cytoskeletal and signaling events, including the regulation of Rac1 GTPase- and myosin II-dependent pathways. Mutations that generate truncated or unstable Coro1A proteins cause immunodeficiencies in both humans and rodents. However, in the case of the peripheral T-cell-deficient (Ptcd) mouse strain, the immunodeficiency is caused by a Glu-26-Lys mutation that targets a surface-exposed residue unlikely to affect the intramolecular architecture and stability of the protein. Here we report that this mutation induces pleiotropic effects in Coro1A protein, including the exacerbation of Coro1A-dependent actin-binding and -bundling activities; the formation of large meshworks of Coro1A(E26K)-decorated filaments endowed with unusual organizational, functional, and staining properties; and the elimination of Coro1A functions associated with both Rac1 and myosin II signaling. By contrast, it does not affect the ability of Coro1A to stimulate the nuclear factor of activated T-cells (NF-AT). Coro1A(E26K) is not a dominant-negative mutant, indicating that its pathological effects are derived from the inability to rescue the complete loss of the wild-type counterpart in cells. These results indicate that Coro1A(E26K) behaves as either a recessive gain-of-function or loss-of-function mutant protein, depending on signaling context and presence of the wild-type counterpart in cells.

| S-EPMC4571328 | biostudies-literature

E-protein regulatory network links TCR signaling to effector Treg cell differentiation.

Project description:T cell antigen receptor (TCR) signaling is essential for the differentiation and maintenance of effector regulatory T (Treg) cells. However, the contribution of individual TCR-dependent genes in Treg cells to the maintenance of immunotolerance remains largely unknown. Here we demonstrate that Treg cells lacking E protein undergo further differentiation into effector cells that exhibit high expression of effector Treg signature genes, including IRF4, ICOS, CD103, KLRG-1, and RORγt. E protein-deficient Treg cells displayed increased stability and enhanced suppressive capacity. Transcriptome and ChIP-seq analyses revealed that E protein directly regulates a large proportion of the genes that are specific to effector Treg cell activation, and importantly, most of the up-regulated genes in E protein-deficient Treg cells are also TCR dependent; this indicates that E proteins comprise a critical gene regulatory network that links TCR signaling to the control of effector Treg cell differentiation and function.

| S-EPMC6410771 | biostudies-literature

Role of Actin Cytoskeleton in Dynamics and Function of the Serotonin<sub>1A</sub> Receptor.

Project description:G protein-coupled receptors (GPCRs) are important membrane proteins in higher eukaryotes that carry out a vast array of cellular signaling and act as major drug targets. The serotonin1A receptor is a prototypical member of the GPCR family and is implicated in neuropsychiatric disorders such as anxiety and depression, besides serving as an important drug target. With an overall goal of exploring the functional consequence of altered receptor dynamics, in this work, we probed the role of the actin cytoskeleton in the dynamics, ligand binding, and signaling of the serotonin1A receptor. We monitored receptor dynamics utilizing single particle tracking, which provides information on relative distribution of receptors in various diffusion modes in addition to diffusion coefficient. We show here that the short-term diffusion coefficient of the receptor increases upon actin destabilization by cytochalasin D. In addition, analysis of individual trajectories shows that there are changes in relative populations of receptors undergoing various types of diffusion upon actin destabilization. The release of dynamic constraint was evident by an increase in the radius of confinement of the receptor upon actin destabilization. The functional implication of such actin destabilization was manifested as an increase in specific agonist binding and downstream signaling, monitored by measuring reduction in cellular cAMP levels. These results bring out the interdependence of GPCR dynamics with cellular signaling.

| S-EPMC7036728 | biostudies-literature

Myosin I links PIP3 signaling to remodeling of the actin cytoskeleton in chemotaxis.

Project description:Class I myosins participate in various interactions between the cell membrane and the cytoskeleton. Several class I myosins preferentially bind to acidic phospholipids, such as phosphatidylserine and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2], through a tail homology 1 (TH1) domain. Here, we show that the second messenger lipid phosphatidylinositol 3,4,5-trisphosphate (PIP3) binds to the TH1 domain of a subset of Dictyostelium class I myosins (ID, IE, and IF) and recruits them to the plasma membrane. The PIP3-regulated membrane recruitment of myosin I promoted chemotaxis and induced chemoattractant-stimulated actin polymerization. Similarly, PIP3 recruited human myosin IF to the plasma membrane upon chemotactic stimulation in a neutrophil cell line. These data suggest a mechanism through which the PIP3 signal is transmitted through myosin I to the actin cytoskeleton.

| S-EPMC3381520 | biostudies-literature

Human trifunctional protein alpha links cardiolipin remodeling to beta-oxidation.

Project description:Cardiolipin (CL) is a mitochondrial membrane phospholipid which plays a key role in apoptosis and supports mitochondrial respiratory chain complexes involved in the generation of ATP. In order to facilitate its role CL must be remodeled with appropriate fatty acids. We previously identified a human monolysocardiolipin acyltransferase activity which remodels CL via acylation of monolysocardiolipin (MLCL) to CL and was identical to the alpha subunit of trifunctional protein (?TFP) lacking the first 227 amino acids. Full length ?TFP is an enzyme that plays a prominent role in mitochondrial ?-oxidation, and in this study we assessed the role, if any, which this metabolic enzyme plays in the remodeling of CL. Purified human recombinant ?TFP exhibited acyl-CoA acyltransferase activity in the acylation of MLCL to CL with linoleoyl-CoA, oleoyl-CoA and palmitoyl-CoA as substrates. Expression of ?TFP increased radioactive linoleate or oleate or palmitate incorporation into CL in HeLa cells. Expression of ?TFP in Barth Syndrome lymphoblasts, which exhibit reduced tetralinoleoyl-CL, elevated linoleoyl-CoA acylation of MLCL to CL in vitro, increased mitochondrial respiratory Complex proteins and increased linoleate-containing species of CL. Knock down of ?TFP in Barth Syndrome lymphoblasts resulted in greater accumulation of MLCL than those with normal ?TFP levels. The results clearly indicate that the human ?TFP exhibits MLCL acyltransferase activity for the resynthesis of CL from MLCL and directly links an enzyme of mitochondrial ?-oxidation to CL remodeling.

| S-EPMC3494688 | biostudies-literature

Coronin 6 regulates acetylcholine receptor clustering through modulating receptor anchorage to actin cytoskeleton.

Project description:The maintenance of a high density of neurotransmitter receptors at the postsynaptic apparatus is critical for efficient neurotransmission. Acetylcholine receptors (AChRs) are neurotransmitter receptors densely packed on the postsynaptic muscle membrane at the neuromuscular junction (NMJ) via anchoring onto the actin cytoskeletal network. However, how the receptor-associated actin is coordinately regulated is not fully understood. We report here that Coronin 6, a newly identified member of the coronin family, is highly enriched at adult NMJs and regulates AChR clustering through modulating the interaction between receptors and the actin cytoskeletal network. Experiments with cultured myotubes reveal that Coronin 6 is important for both agrin- and laminin-induced AChR clustering. Furthermore, Coronin 6 forms a complex with AChRs and actin in a manner dependent on its C-terminal region and a conserved Arg(29) residue at the N terminus, both of which are critical for the cytoskeletal anchorage of AChRs. Importantly, in vivo knockdown of Coronin 6 in mouse skeletal muscle fibers leads to destabilization of AChR clusters. Together, these findings demonstrate that Coronin 6 is a critical regulator of AChR clustering at the postsynaptic region of the NMJs through modulating the receptor-anchored actin cytoskeleton.

| S-EPMC6802748 | 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