Browse
Submit Data
Databases
API
Help

Dataset Information

15 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

KCNE4-dependent functional consequences of Kv1.3-related leukocyte physiology.

ABSTRACT: The voltage-dependent potassium channel Kv1.3 plays essential roles in the immune system, participating in leukocyte activation, proliferation and apoptosis. The regulatory subunit KCNE4 acts as an ancillary peptide of Kv1.3, modulates K⁺ currents and controls channel abundance at the cell surface. KCNE4-dependent regulation of the oligomeric complex fine-tunes the physiological role of Kv1.3. Thus, KCNE4 is crucial for Ca²⁺-dependent Kv1.3-related leukocyte functions. To better understand the role of KCNE4 in the regulation of the immune system, we manipulated its expression in various leukocyte cell lines. Jurkat T lymphocytes exhibit low KCNE4 levels, whereas CY15 dendritic cells, a model of professional antigen-presenting cells, robustly express KCNE4. When the cellular KCNE4 abundance was increased in T cells, the interaction between KCNE4 and Kv1.3 affected important T cell physiological features, such as channel rearrangement in the immunological synapse, cell growth, apoptosis and activation, as indicated by decreased IL-2 production. Conversely, ablation of KCNE4 in dendritic cells augmented proliferation. Furthermore, the LPS-dependent activation of CY15 cells, which induced Kv1.3 but not KCNE4, increased the Kv1.3-KCNE4 ratio and increased the expression of free Kv1.3 without KCNE4 interaction. Our results demonstrate that KCNE4 is a pivotal regulator of the Kv1.3 channelosome, which fine-tunes immune system physiology by modulating Kv1.3-associated leukocyte functions.

SUBMITTER: Vallejo-Gracia A

PROVIDER: S-EPMC8285421 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Functional Consequences of the Variable Stoichiometry of the Kv1.3-KCNE4 Complex.

Project description:The voltage-gated potassium channel Kv1.3 plays a crucial role during the immune response. The channel forms oligomeric complexes by associating with several modulatory subunits. KCNE4, one of the five members of the KCNE family, binds to Kv1.3, altering channel activity and membrane expression. The association of KCNEs with Kv channels is the subject of numerous studies, and the stoichiometry of such associations has led to an ongoing debate. The number of KCNE4 subunits that can interact and modulate Kv1.3 is unknown. KCNE4 transfers important elements to the Kv1.3 channelosome that negatively regulate channel function, thereby fine-tuning leukocyte physiology. The aim of this study was to determine the stoichiometry of the functional Kv1.3-KCNE4 complex. We demonstrate that as many as four KCNE4 subunits can bind to the same Kv1.3 channel, indicating a variable Kv1.3-KCNE4 stoichiometry. While increasing the number of KCNE4 subunits steadily slowed the activation of the channel and decreased the abundance of Kv1.3 at the cell surface, the presence of a single KCNE4 peptide was sufficient for the cooperative enhancement of the inactivating function of the channel. This variable architecture, which depends on KCNE4 availability, differentially affects Kv1.3 function. Therefore, our data indicate that the physiological remodeling of KCNE4 triggers functional consequences for Kv1.3, thus affecting cell physiology.

| S-EPMC7290415 | biostudies-literature

Calmodulin-dependent KCNE4 dimerization controls membrane targeting.

Project description:The voltage-dependent potassium channel Kv1.3 participates in the immune response. Kv1.3 is essential in different cellular functions, such as proliferation, activation and apoptosis. Because aberrant expression of Kv1.3 is linked to autoimmune diseases, fine-tuning its function is crucial for leukocyte physiology. Regulatory KCNE subunits are expressed in the immune system, and KCNE4 specifically tightly regulates Kv1.3. KCNE4 modulates Kv1.3 currents slowing activation, accelerating inactivation and retaining the channel at the endoplasmic reticulum (ER), thereby altering its membrane localization. In addition, KCNE4 genomic variants are associated with immune pathologies. Therefore, an in-depth knowledge of KCNE4 function is extremely relevant for understanding immune system physiology. We demonstrate that KCNE4 dimerizes, which is unique among KCNE regulatory peptide family members. Furthermore, the juxtamembrane tetraleucine carboxyl-terminal domain of KCNE4 is a structural platform in which Kv1.3, Ca2+/calmodulin (CaM) and dimerizing KCNE4 compete for multiple interaction partners. CaM-dependent KCNE4 dimerization controls KCNE4 membrane targeting and modulates its interaction with Kv1.3. KCNE4, which is highly retained at the ER, contains an important ER retention motif near the tetraleucine motif. Upon escaping the ER in a CaM-dependent pattern, KCNE4 follows a COP-II-dependent forward trafficking mechanism. Therefore, CaM, an essential signaling molecule that controls the dimerization and membrane targeting of KCNE4, modulates the KCNE4-dependent regulation of Kv1.3, which in turn fine-tunes leukocyte physiology.

| S-EPMC8263776 | biostudies-literature

Ligand recognition specificity of leukocyte integrin ?M?2 (Mac-1, CD11b/CD18) and its functional consequences.

Project description:The broad recognition specificity exhibited by integrin ?(M)?2 (Mac-1, CD11b/CD18) has allowed this adhesion receptor to play innumerable roles in leukocyte biology, yet we know little about how and why ?(M)?2 binds its multiple ligands. Within ?(M)?2, the ?(M)I-domain is responsible for integrin's multiligand binding properties. To identify its recognition motif, we screened peptide libraries spanning sequences of many known protein ligands for ?(M)I-domain binding and also selected the ?(M)I-domain recognition sequences by phage display. Analyses of >1400 binding and nonbinding peptides derived from peptide libraries showed that a key feature of the ?(M)I-domain recognition motif is a small core consisting of basic amino acids flanked by hydrophobic residues. Furthermore, the peptides selected by phage display conformed to a similar pattern. Identification of the recognition motif allowed the construction of an algorithm that reliably predicts the ?(M)I-domain binding sites in the ?(M)?2 ligands. The recognition specificity of the ?(M)I-domain resembles that of some chaperones, which allows it to bind segments exposed in unfolded proteins. The disclosure of the ?(M)?2 binding preferences allowed the prediction that cationic host defense peptides, which are strikingly enriched in the ?(M)I-domain recognition motifs, represent a new class of ?(M)?2 ligands. This prediction has been tested by examining the interaction of ?(M)?2 with the human cathelicidin peptide LL-37. LL-37 induced a potent ?(M)?2-dependent cell migratory response and caused activation of ?(M)?2 on neutrophils. The newly revealed recognition specificity of ?(M)?2 toward unfolded protein segments and cationic proteins and peptides suggests that ?(M)?2 may serve as a previously proposed "alarmin" receptor with important roles in innate host defense.

| S-EPMC4532391 | biostudies-literature

Dissecting the Functional Consequences of De Novo DNA Methylation Dynamics in Human Motor Neuron Differentiation and Physiology.

Project description:The somatic DNA methylation (DNAme) landscape is established early in development but remains highly dynamic within focal regions that overlap with gene regulatory elements. The significance of these dynamic changes, particularly in the central nervous system, remains unresolved. Here, we utilize a powerful human embryonic stem cell differentiation model for the generation of motor neurons (MNs) in combination with genetic mutations in the de novo DNAme machinery. We quantitatively dissect the role of DNAme in directing somatic cell fate with high-resolution genome-wide bisulfite-, bulk-, and single-cell-RNA sequencing. We find defects in neuralization and MN differentiation in DNMT3A knockouts (KO) that can be rescued by the targeting of DNAme to key developmental loci using catalytically inactive dCas9. We also find decreased dendritic arborization and altered electrophysiological properties in DNMT3A KO MNs. Our work provides a list of DNMT3A-regulated targets and a mechanistic link between de novo DNAme, cellular differentiation, and human MN function.

| S-EPMC6535433 | biostudies-literature

Necrosis- and apoptosis-related Met cleavages have divergent functional consequences.

Project description:Upon activation by its ligand hepatocyte growth factor/scatter factor, the receptor tyrosine kinase Met promotes survival, proliferation, and migration of epithelial cells during embryogenesis. Deregulated Met signaling can also promote cancer progression and metastasis. Met belongs to the functional family of dependence receptors whose activity switches from pro-survival to pro-apoptotic during apoptosis upon caspase cleavage. Although apoptosis resistance is a hallmark of cancer cells, some remain sensitive to other cell death processes, including necrosis induced by calcium stress. The role and fate of Met during necrotic cell death are unknown. Following treatment with calcium ionophores, cell lines and primary cells undergo necrosis, and the full-length Met receptor is efficiently degraded. This degradation is achieved by double cleavage of Met in its extracellular domain by a metalloprotease of the A disintegrin and metalloproteinase (ADAM) family and in its intracellular domain by calpains (calcium-dependent proteases). These cleavages separate the Met extracellular region from its kinase domain, thus preventing Met activity and its potential pro-survival activity. Although the intracellular fragment is very similar to the fragment generated by caspases, it displays no pro-apoptotic property, likely because of the presence of the last few amino acids of Met, known to inhibit this pro-apoptotic function. The fragments identified here are observed in lung tumors overexpressing the Met receptor, along with fragments previously identified, suggesting that proteolytic cleavages of Met are involved in its degradation in tumor tissues. Thus, Met is a modulator of necrosis, able to protect cells when activated by its ligand but efficiently degraded by proteolysis when this process is engaged.

| S-EPMC4669710 | biostudies-literature

Dissecting the Functional Consequences of de Novo DNA Methylation Dynamics in Human Motor Neuron Differentiation and Physiology

Project description:DNA methylation is a well studied, yet still incompletely understood component of the multi-layered epigenome. The somatic DNA methylation landscape is established early in development, but remains highly dynamic within focal regions that tend to overlap with gene regulatory elements. The functional significance of these dynamic changes remains unresolved. Here we utilized a powerful human ESC differentiation model for the generation of motor neurons (MNs) in combination with genetic mutations in the de novo DNA methylation machinery to dissect the role of DNA methylation in directing somatic cell fate. We quantitatively and in high-resolution measure the molecular and functional consequences of epigenetic perturbation. We find defects in neuralization and MN development. We also observe decreased dendritic arborization and altered electrophysiological properties in DNMT3A KO MNs. Our work provides a specific list of epigenetically deregulated targets and a mechanistic link between de novo DNA methylation, cellular differentiation and human MN function.

2018-03-15 | GSE90553 | GEO

Structural and functional consequences of age-related isomerization in α-crystallins.

Project description:Long-lived proteins are subject to spontaneous degradation and may accumulate a range of modifications over time, including subtle alterations such as side-chain isomerization. Recently, tandem MS has enabled identification and characterization of such peptide isomers, including those differing only in chirality. However, the structural and functional consequences of these perturbations remain largely unexplored. Here, we examined the impact of isomerization of aspartic acid or epimerization of serine at four sites mapping to crucial oligomeric interfaces in human αA- and αB-crystallin, the most abundant chaperone proteins in the eye lens. To characterize the effect of isomerization on quaternary assembly, we utilized synthetic peptide mimics, enzyme assays, molecular dynamics calculations, and native MS experiments. The oligomerization of recombinant forms of αA- and αB-crystallin that mimic isomerized residues deviated from native behavior in all cases. Isomerization also perturbs recognition of peptide substrates, either enhancing or inhibiting kinase activity. Specifically, epimerization of serine (αASer-162) dramatically weakened inter-subunit binding. Furthermore, phosphorylation of αBSer-59, known to play an important regulatory role in oligomerization, was severely inhibited by serine epimerization and altered by isomerization of nearby αBAsp-62. Similarly, isomerization of αBAsp-109 disrupted a vital salt bridge with αBArg-120, a contact that when broken has previously been shown to yield aberrant oligomerization and aggregation in several disease-associated variants. Our results illustrate how isomerization of amino acid residues, which may seem to be only a minor structural perturbation, can disrupt native structural interactions with profound consequences for protein assembly and activity.

| S-EPMC6514633 | biostudies-literature

KCNE4 juxtamembrane region is required for interaction with calmodulin and for functional suppression of KCNQ1.

Project description:Voltage-gated potassium (K(V)) channels, such as KCNQ1 (K(V)7.1), are modulated by accessory subunits and regulated by intracellular second messengers. Accessory subunits belonging to the KCNE family exert diverse functional effects on KCNQ1, have been implicated in the pathogenesis of various genetic disorders of heart rhythm, and contribute to transducing intracellular signaling events into changes in K(V) channel activity. We investigated the interactions between calmodulin (CaM), the ubiquitous Ca(2+)-transducing protein that binds and confers Ca(2+) sensitivity to the biophysical properties of KCNQ1, and KCNE4. These studies were motivated by the observed similarities between the suppression of KCNQ1 function by pharmacological disruption of KCNQ1-CaM interactions and the effects of KCNE4 co-expression on the channel. We determined that KCNE4, but not KCNE1, can biochemically interact with CaM and that this interaction is Ca(2+)-dependent and requires a tetraleucine motif in the juxtamembrane region of the KCNE4 C terminus. Furthermore, disruption of the KCNE4-CaM interaction either by mutagenesis of the tetraleucine motif or by acute Ca(2+) chelation impairs the ability of KCNE4 to inhibit KCNQ1. Our findings have potential relevance to KCNQ1 regulation both by KCNE accessory subunits and by an important intracellular signaling molecule.

| S-EPMC3039368 | biostudies-literature

Functional consequences of experience-dependent plasticity on tactile perception following perceptual learning.

Project description:Continuous training enhances perceptual discrimination and promotes neural changes in areas encoding the experienced stimuli. This type of experience-dependent plasticity has been demonstrated in several sensory and motor systems. Particularly, non-human primates trained to detect consecutive tactile bar indentations across multiple digits showed expanded excitatory receptive fields (RFs) in somatosensory cortex. However, the perceptual implications of these anatomical changes remain undetermined. Here, we trained human participants for 9 days on a tactile task that promoted expansion of multi-digit RFs. Participants were required to detect consecutive indentations of bar stimuli spanning multiple digits. Throughout the training regime we tracked participants' discrimination thresholds on spatial (grating orientation) and temporal tasks on the trained and untrained hands in separate sessions. We hypothesized that training on the multi-digit task would decrease perceptual thresholds on tasks that require stimulus processing across multiple digits, while also increasing thresholds on tasks requiring discrimination on single digits. We observed an increase in orientation thresholds on a single digit. Importantly, this effect was selective for the stimulus orientation and hand used during multi-digit training. We also found that temporal acuity between digits improved across trained digits, suggesting that discriminating the temporal order of multi-digit stimuli can transfer to temporal discrimination of other tactile stimuli. These results suggest that experience-dependent plasticity following perceptual learning improves and interferes with tactile abilities in manners predictive of the task and stimulus features used during training.

| S-EPMC5028271 | biostudies-literature

Diet-induced obesity resistance of Kv1.3-/- mice is olfactory bulb dependent.

Project description:Gene-targeted deletion of the voltage-gated potassium channel, Kv1.3 (Kv1.3-/-), increases olfactory sensitivity and discriminatory ability, and causes resistance to diet-induced obesity (DIO) in mice. The present study aimed to determine whether the enhanced olfactory ability of the Kv1.3-/- mouse contributes to the resistance to DIO. Kv1.3+/+ and Kv1.3-/- mice were subject to bilateral olfactory bulbectomy (OBX) or sham surgery at 9?weeks of age and placed on either a control chow diet or a 32% moderately high-fat diet (MHF). Caloric and water intake, locomotor activity and oxygen consumption were monitored after 5?weeks of diet treatment. At the end of 26?weeks of diet treatment, fat pad weight and blood chemistry were evaluated. Kv1.3+/+ mice exhibited a significant increase in weight, adiposity, fasting glucose and fasting leptin in response to the MHF-diet, with or without OBX. When treated with a MHF-diet, Kv1.3-/- mice gained significantly less weight than Kv1.3+/+ mice and exhibited a significant increase in light phase metabolism. OBX of Kv1.3-/- mice prevented the resistance to DIO and concomitant up-regulation of light phase metabolism at the same time as decreasing dark phase metabolism and total energy expenditure. These findings suggest that pathways activated in Kv1.3-/- that increased energy expenditure and led to resistance to DIO are olfactory bulb dependent. Thus, these findings add to a growing body of evidence suggesting that the olfactory system can modulate the pathways involved in the regulation of energy balance.

| S-EPMC3391345 | 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