scholarly journals Calmodulin-dependent KCNE4 dimerization controls membrane targeting

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sara R. Roig ◽  
Laura Solé ◽  
Silvia Cassinelli ◽  
Magalí Colomer-Molera ◽  
Daniel Sastre ◽  
...  
Keyword(s):  
Immune System ◽  
Fine Tuning ◽  
Membrane Targeting ◽  
Cellular Functions ◽  
Aberrant Expression ◽  
Peptide Family ◽  
Er Retention ◽  
Voltage Dependent ◽  
System Physiology ◽  
Multiple Interaction

AbstractThe 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.

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

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Albert Vallejo-Gracia ◽  
Daniel Sastre ◽  
Magalí Colomer-Molera ◽  
Laura Solé ◽  
María Navarro-Pérez ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune System ◽  
Immunological Synapse ◽  
Physiological Role ◽  
Regulatory Subunit ◽  
Voltage Dependent ◽  
Functional Consequences ◽  
System Physiology ◽  
Antigen Presenting

AbstractThe 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.

scholarly journals Electrochemical Biosensors for Cytokine Profiling: Recent Advancements and Possibilities in the Near Future

Biosensors ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 94
Author(s):  
Nirmita Dutta ◽  
Peter B. Lillehoj ◽  
Pedro Estrela ◽  
Gorachand Dutta
Keyword(s):  
Immune System ◽  
Cost Effective ◽  
Anomalous Behavior ◽  
Quantitative Detection ◽  
Electrochemical Biosensors ◽  
Aberrant Expression ◽  
Detection Techniques ◽  
Short Period ◽  
User Friendly ◽  
Cytokine Profiling

Cytokines are soluble proteins secreted by immune cells that act as molecular messengers relaying instructions and mediating various functions performed by the cellular counterparts of the immune system, by means of a synchronized cascade of signaling pathways. Aberrant expression of cytokines can be indicative of anomalous behavior of the immunoregulatory system, as seen in various illnesses and conditions, such as cancer, autoimmunity, neurodegeneration and other physiological disorders. Cancer and autoimmune diseases are particularly adept at developing mechanisms to escape and modulate the immune system checkpoints, reflected by an altered cytokine profile. Cytokine profiling can provide valuable information for diagnosing such diseases and monitoring their progression, as well as assessing the efficacy of immunotherapeutic regiments. Toward this goal, there has been immense interest in the development of ultrasensitive quantitative detection techniques for cytokines, which involves technologies from various scientific disciplines, such as immunology, electrochemistry, photometry, nanotechnology and electronics. This review focusses on one aspect of this collective effort: electrochemical biosensors. Among the various types of biosensors available, electrochemical biosensors are one of the most reliable, user-friendly, easy to manufacture, cost-effective and versatile technologies that can yield results within a short period of time, making it extremely promising for routine clinical testing.

scholarly journals Autoimmune Responses in Oncology: Causes and Significance

2021 ◽  
Vol 22 (15) ◽  
pp. 8030
Author(s):  
Halin Bareke ◽  
Pablo Juanes-Velasco ◽  
Alicia Landeira-Viñuela ◽  
Angela-Patricia Hernandez ◽  
Juan Jesús Cruz ◽  
...  
Keyword(s):  
Cancer Immunotherapy ◽  
Protein Microarrays ◽  
Cross Reactivity ◽  
Fine Tuning ◽  
Cancer Treatments ◽  
Aberrant Expression ◽  
Specificity And Sensitivity ◽  
Anti Cancer ◽  
Life Threatening ◽  
Considerable Impact

Specific anti-tumor immune responses have proven to be pivotal in shaping tumorigenesis and tumor progression in solid cancers. These responses can also be of an autoimmune nature, and autoantibodies can sometimes be present even before the onset of clinically overt disease. Autoantibodies can be generated due to mutated gene products, aberrant expression and post-transcriptional modification of proteins, a pro-immunogenic milieu, anti-cancer treatments, cross-reactivity of tumor-specific lymphocytes, epitope spreading, and microbiota-related and genetic factors. Understanding these responses has implications for both basic and clinical immunology. Autoantibodies in solid cancers can be used for early detection of cancer as well as for biomarkers of prognosis and treatment response. High-throughput techniques such as protein microarrays make parallel detection of multiple autoantibodies for increased specificity and sensitivity feasible, affordable, and quick. Cancer immunotherapy has revolutionized cancer treatments and has made a considerable impact on reducing cancer-associated morbidity and mortality. However, immunotherapeutic interventions such as immune checkpoint inhibition can induce immune-related toxicities, which can even be life-threatening. Uncovering the reasons for treatment-induced autoimmunity can lead to fine-tuning of cancer immunotherapy approaches to evade toxic events while inducing an effective anti-tumor immune response.

scholarly journals Antimicrobial Nodule-Specific Cysteine-Rich Peptides Induce Membrane Depolarization-Associated Changes in the Transcriptome of Sinorhizobium meliloti

2013 ◽  
Vol 79 (21) ◽  
pp. 6737-6746 ◽  
Author(s):  
Hilda Tiricz ◽  
Attila Szűcs ◽  
Attila Farkas ◽  
Bernadett Pap ◽  
Rui M. Lima ◽  
...  
Keyword(s):  
Stress Responses ◽  
Sinorhizobium Meliloti ◽  
Antimicrobial Agents ◽  
Cellular Functions ◽  
Gram Positive ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Peptide Family ◽  
Wide Range ◽  
Natural Target

ABSTRACTLeguminous plants establish symbiosis with nitrogen-fixing alpha- and betaproteobacteria, collectively called rhizobia, which provide combined nitrogen to support plant growth. Members of the inverted repeat-lacking clade of legumes impose terminal differentiation on their endosymbiotic bacterium partners with the help of the nodule-specific cysteine-rich (NCR) peptide family composed of close to 600 members. Among the few tested NCR peptides, cationic ones had antirhizobial activity measured by reduction or elimination of the CFU and uptake of the membrane-impermeable dye propidium iodide. Here, the antimicrobial spectrum of two of these peptides, NCR247 and NCR335, was investigated, and their effect on the transcriptome of the natural targetSinorhizobium melilotiwas characterized. Both peptides were able to kill quickly a wide range of Gram-negative and Gram-positive bacteria; however, their spectra were only partially overlapping, and differences were found also in their efficacy on given strains, indicating that the actions of NCR247 and NCR335 might be similar though not identical. Treatment ofS. meliloticultures with either peptide resulted in a quick downregulation of genes involved in basic cellular functions, such as transcription-translation and energy production, as well as upregulation of genes involved in stress and oxidative stress responses and membrane transport. Similar changes provoked mainly in Gram-positive bacteria by antimicrobial agents were coupled with the destruction of membrane potential, indicating that it might also be a common step in the bactericidal actions of NCR247 and NCR335.

scholarly journals Myosin-II activity generates a dynamic steady state with continuous actin turnover in a minimal actin cortex

2018 ◽  
Author(s):  
Sonal ◽  
Kristina A. Ganzinger ◽  
Sven K. Vogel ◽  
Jonas Mücksch ◽  
Philipp Blumhardt ◽  
...  
Keyword(s):  
Steady State ◽  
Actin Polymerization ◽  
Myosin Ii ◽  
Fine Tuning ◽  
Cellular Functions ◽  
Actin Cortex ◽  
Actin Turnover ◽  
Cytoskeletal Dynamics

ABSTRACTDynamic reorganization of the actomyosin cytoskeleton allows a fine-tuning of cell shape that is vital to many cellular functions. It is well established that myosin-II motors generate the forces required for remodeling the cell surface by imparting contractility to actin networks. An additional, less understood, role of myosin-II in cytoskeletal dynamics is believed to be in the regulation of actin turnover; it has been proposed that myosin activity increases actin turnover in various cellular contexts, presumably by contributing to disassembly. In vitro reconstitution of actomyosin networks has confirmed the role of myosin in actin network disassembly, but factors such as diffusional constraints and the use of stabilized filaments have thus far limited the observation of myosin-assisted actin turnover in these networks. Here, we present the reconstitution of a minimal dynamic actin cortex where actin polymerization is catalyzed on the membrane in the presence of myosin-II activity. We demonstrate that myosin activity leads to disassembly and redistribution in this simplified cortex. Consequently, a new dynamic steady state emerges in which actin filaments undergo constant turnover. Our findings suggest a multi-faceted role of myosin-II in fast remodeling of the eukaryotic actin cortex.

Bombesin-evoked gastrin release and calcium signaling in human antral G cells in culture

1999 ◽  
Vol 276 (1) ◽  
pp. G227-G237 ◽  
Author(s):  
Paul E. Squires ◽  
R. Mark Meloche ◽  
Alison M. J. Buchan
Keyword(s):  
Cell Culture ◽  
Calcium Signaling ◽  
Gastrin Release ◽  
Voltage Gated ◽  
Gastrin Releasing Peptide ◽  
G Cells ◽  
Peptide Family ◽  
Inositol 1,4,5 Trisphosphate ◽  
Voltage Dependent ◽  
Intracellular Ca

Amplification of mRNA from a human antral cell culture preparation demonstrated the presence of two receptors of the bombesin and gastrin-releasing peptide family, GRPR-1 and BRS-3. Single cell microfluorometry demonstrated that most cells that exhibited bombesin-evoked changes in intracellular Ca2+ concentration were gastrin immunoreactive, indicating that antral G cells express the GRPR subtype. There were two components to the intracellular Ca2+ response: an initial nitrendipine-insensitive mobilization followed by a sustained phase that was inhibited by removal of extracellular Ca2+ and 20 mM caffeine and was partially inhibited by 10 μM nitrendipine. Preexposure of cells to thapsigargin and caffeine prevented the response to bombesin, indicating activation of inositol 1,4,5-trisphosphate (IP3)-sensitive stores. Gastrin release could be partially reversed by removal of extracellular Ca2+ and blockade of L-type voltage-dependent Ca2+ channels, indicating that a component of the secretory response to bombesin was dependent on Ca2+ influx. These data demonstrated that bombesin-stimulated gastrin release from human antral G cells resulted from activation of GRPRs and involved both release of intracellular Ca2+ and influx of extracellular Ca2+through a combination of L-type voltage-gated and IP3-gated Ca2+ channels.

scholarly journals The Circadian NAD+Metabolism: Impact on Chromatin Remodeling and Aging

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Yasukazu Nakahata ◽  
Yasumasa Bessho
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Cell Fate ◽  
Chromatin Remodeling ◽  
Expression Patterns ◽  
Fine Tuning ◽  
Cellular Functions ◽  
Nad Metabolism ◽  
Structure Changes ◽  
Age Related

Gene expression is known to be a stochastic phenomenon. The stochastic gene expression rate is thought to be altered by topological change of chromosome and/or by chromatin modifications such as acetylation and methylation. Changes in mechanical properties of chromosome/chromatin by soluble factors, mechanical stresses from the environment, or metabolites determine cell fate, regulate cellular functions, or maintain cellular homeostasis. Circadian clock, which drives the expression of thousands of genes with 24-hour rhythmicity, has been known to be indispensable for maintaining cellular functions/homeostasis. During the last decade, it has been demonstrated that chromatin also undergoes modifications with 24-hour rhythmicity and facilitates the fine-tuning of circadian gene expression patterns. In this review, we cover data which suggests that chromatin structure changes in a circadian manner and that NAD+is the key metabolite for circadian chromatin remodeling. Furthermore, we discuss the relationship among circadian clock, NAD+metabolism, and aging/age-related diseases. In addition, the interventions of NAD+metabolism for the prevention and treatment of aging and age-related diseases are also discussed.

scholarly journals The endocytic pathways of Dictyostelium discoideum

2019 ◽  
Vol 63 (8-9-10) ◽  
pp. 461-471 ◽  
Author(s):  
James H. Vines ◽  
Jason S. King
Keyword(s):  
Immune System ◽  
Maturation Process ◽  
Cellular Functions ◽  
Social Amoeba ◽  
The Social ◽  
Evolutionary Context ◽  
The Many ◽  
Membrane Components ◽  
Mammalian Immune System ◽  
Endocytic Pathways

The formation and processing of vesicles from the cell surface serves many important cellular functions ranging from nutrient acquisition to regulating the turnover of membrane components and signalling. In this article, we summarise the endocytic pathways of the social amoeba Dictyostelium from the clathrin-dependent and independent internalisation of surface components to the engulfment of bacteria or fluid by phagocytosis and macropinocytosis respectively. Due to similarities with the professional phagocytes of the mammalian immune system Dictyostelium has been extensively used to investigate the complex remodelling and trafficking events that occur as phagosomes and macropinosomes transit through the cell. Here we discuss what is known about this maturation process in order to kill any potential pathogens and obtain nutrients for growth. Finally, we aim to put these studies in evolutionary context and highlight some of the many questions that remain in our understanding of these complex and important pathways.

Adenine nucleotides as paracrine mediators and intracellular second messengers in immunity and inflammation

2019 ◽  
Vol 47 (1) ◽  
pp. 329-337 ◽  
Author(s):  
Ralf Fliegert ◽  
Jörg Heeren ◽  
Friedrich Koch-Nolte ◽  
Viacheslav O. Nikolaev ◽  
Christian Lohr ◽  
...  
Keyword(s):  
Immune System ◽  
T Lymphocytes ◽  
Immune Responses ◽  
Nicotinamide Adenine Dinucleotide ◽  
Adenine Nucleotides ◽  
Second Messengers ◽  
Cellular Responses ◽  
Fine Tuning ◽  
Inflammatory Processes ◽  
Intracellular Second Messengers

Abstract Adenine nucleotides (AdNs) play important roles in immunity and inflammation. Extracellular AdNs, such as adenosine triphosphate (ATP) or nicotinamide adenine dinucleotide (NAD) and their metabolites, act as paracrine messengers by fine-tuning both pro- and anti-inflammatory processes. Moreover, intracellular AdNs derived from ATP or NAD play important roles in many cells of the immune system, including T lymphocytes, macrophages, neutrophils and others. These intracellular AdNs are signaling molecules that transduce incoming signals into meaningful cellular responses, e.g. activation of immune responses against pathogens.

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