Optimal ligand discrimination by asymmetric dimerization and turnover of interferon receptors

2021 ◽  
Vol 118 (37) ◽  
pp. e2103939118
Author(s):  
Patrick Binder ◽  
Nikolas D. Schnellbächer ◽  
Thomas Höfer ◽  
Nils B. Becker ◽  
Ulrich S. Schwarz
Keyword(s):  
Defense Mechanisms ◽  
Antiviral Defense ◽  
Discrimination Power ◽  
Receptor System ◽  
Information Theoretic ◽  
Single Receptor ◽  
Ligand Type ◽  
Theoretic Problem ◽  
Multicellular Organisms ◽  
Receptor Turnover

In multicellular organisms, antiviral defense mechanisms evoke a reliable collective immune response despite the noisy nature of biochemical communication between tissue cells. A molecular hub of this response, the interferon I receptor (IFNAR), discriminates between ligand types by their affinity regardless of concentration. To understand how ligand type can be decoded robustly by a single receptor, we frame ligand discrimination as an information-theoretic problem and systematically compare the major classes of receptor architectures: allosteric, homodimerizing, and heterodimerizing. We demonstrate that asymmetric heterodimers achieve the best discrimination power over the entire physiological range of local ligand concentrations. This design enables sensing of ligand presence and type, and it buffers against moderate concentration fluctuations. In addition, receptor turnover, which drives the receptor system out of thermodynamic equilibrium, allows alignment of activation points for ligands of different affinities and thereby makes ligand discrimination practically independent of concentration. IFNAR exhibits this optimal architecture, and our findings thus suggest that this specialized receptor can robustly decode digital messages carried by its different ligands.

scholarly journals MOLECULAR EVOLUTION OF GPCRS: CRH/CRH receptors

2014 ◽  
Vol 52 (3) ◽  
pp. T43-T60 ◽  
Author(s):  
David A Lovejoy ◽  
Belinda S W Chang ◽  
Nathan R Lovejoy ◽  
Jon del Castillo
Keyword(s):  
Stress Response ◽  
Molecular System ◽  
Peptide Hormone ◽  
Nutrient Acquisition ◽  
Energy Usage ◽  
Receptor System ◽  
Genome Duplications ◽  
Complex Forms ◽  
Multicellular Organisms ◽  
Crh Receptors

Corticotrophin-releasing hormone (CRH) is the pivotal neuroendocrine peptide hormone associated with the regulation of the stress response in vertebrates. However, CRH-like peptides are also found in a number of invertebrate species. The origin of this peptide can be traced to a common ancestor of lineages leading to chordates and to arthropods, postulated to occur some 500 million years ago. Evidence indicates the presence of a single CRH-like receptor and a soluble binding protein system that acted to transduce and regulate the actions of the early CRH peptide. In vertebrates, genome duplications led to the divergence of CRH receptors into CRH1 and CRH2 forms in tandem with the development of four paralogous ligand lineages that included CRH; urotensin I/urocortin (Ucn), Ucn2 and Ucn3. In addition, taxon-specific genome duplications led to further local divergences in CRH ligands and receptors. Functionally, the CRH ligand–receptor system evolved initially as a molecular system to integrate early diuresis and nutrient acquisition. As multicellular organisms evolved into more complex forms, this ligand–receptor system became integrated with the organismal stress response to coordinate homoeostatic challenges with internal energy usage. In vertebrates, CRH and the CRH1 receptor became associated with the hypothalamo-pituitary–adrenal/interrenal axis and the initial stress response, whereas the CRH2 receptor was selected to play a greater role in diuresis, nutrient acquisition and the latter aspects of the stress response.

scholarly journals Proteinase-Activated Receptor-2 Agonist Activates Anti-Influenza Mechanisms and Modulates IFNγ-Induced Antiviral Pathways in Human Neutrophils

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Micha Feld ◽  
Victoria Shpacovitch ◽  
Christina Ehrhardt ◽  
Michaela Fastrich ◽  
Tobias Goerge ◽  
...  
Keyword(s):  
Influenza A ◽  
Defense Mechanisms ◽  
Inflammatory Diseases ◽  
Human Neutrophils ◽  
Antiviral Resistance ◽  
Antiviral Defense ◽  
Ros Production ◽  
Oxygen Species ◽  
Human Leukocytes ◽  
Antiviral Responses

Proteinase-activated receptor-2 (PAR2) is expressed by human leukocytes and participates in the development of inflammatory diseases. Recent studies demonstrated an ability of PAR2agonist to enhance IFNγ-induced antiviral responses of human leukocytes. However, the precise cellular antiviral defense mechanisms triggered in leukocytes after stimulation with IFNγand/or PAR2agonist remain elusive. Therefore, we aimed to identify neutrophil defense mechanisms involved in antiviral resistance. Here we demonstrated that PAR2agonist enhanced IFNγ-related reduction of influenza A virus (IAV) replication in human neutrophils. PAR2-mediated decrease in IAV replication was associated with reduced NS-1 transcription. Moreover, PAR2-dependent neutrophil activation resulted in enhanced myeloperoxidase degranulation and extracellular myeloperoxidase disrupted IAV. The production of ROS was elevated in response to PAR2activation. Interestingly, IFNγdid not influence both effects: PAR2agonist-triggered myeloperoxidase (MPO) release and reactive oxygen species (ROS) production, which are known to limit IAV infections. In contrast, orthomyxovirus resistance gene A (MxA) protein expression was synergistically elevated through PAR2agonist and IFNγin neutrophils. Altogether, these findings emphasize two PAR2-controlled antiviral mechanisms that are independent of or modulated by IFNγ.

scholarly journals Inhibition of Intracellular Antiviral Defense Mechanisms Augments Lentiviral Transduction of Human Natural Killer Cells: Implications for Gene Therapy

2012 ◽  
Vol 23 (10) ◽  
pp. 1090-1100 ◽  
Author(s):  
Tolga Sutlu ◽  
Sanna Nyström ◽  
Mari Gilljam ◽  
Birgitta Stellan ◽  
Steven E. Applequist ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Natural Killer Cells ◽  
Natural Killer ◽  
Defense Mechanisms ◽  
Antiviral Defense ◽  
Killer Cells ◽  
Lentiviral Transduction ◽  
Human Natural Killer Cells

scholarly journals Molecular and cellular mechanisms of central nervous system alteration in COVID-19

2020 ◽  
Vol 9 (3) ◽  
pp. 72-85
Author(s):  
N. T. Alexeeva ◽  
D. A. Sokolov ◽  
D. B. Nikityuk ◽  
S. V. Klochkova ◽  
A. G. Kvaratskheliya
Keyword(s):  
Immune Cells ◽  
Defense Mechanisms ◽  
Retrograde Axonal Transport ◽  
Antiviral Defense ◽  
Vagus Nerves ◽  
Cellular Mechanisms ◽  
Inflammatory Reactions ◽  
Viral Particles ◽  
The Brain

The ongoing coronavirus disease 2019 (COVID-19) pandemic dictates the need to study the molecular and cellular mechanisms of interaction between the pathogen and the human body. The manifestation of neurological symptoms in some patients with COVID-19 is a problem for neuroscientists due to the insufficiently understood pathomorphogenesis of the disease. This review systematizes the literature data reflecting the ways of penetration of SARS-CoV-2 into the brain, features of its interaction with neurons, neuroglia, and immune cells. It has been shown that the main mechanisms of SARS-CoV-2 neuroinvasion are presumably retrograde axonal transport along the fibers of the olfactory and vagus nerves; penetration through the damaged blood-brain barrier (BBB) or migration of immunocompetent cells containing viral particles through the intact BBB. It was found that virusinducible neuronal death is caused not only by a direct cytotoxic effect, but also due to dysregulation of the reninangiotensin system of the brain and the release of a large amount of inflammatory cytokines as a manifestation of a “cytokine storm”. The participation of neuroglial cells in the initiation and maintenance of neuroinflammatory and neurodegenerative processes due to the activation of their proinflammatory phenotype has been demonstrated. The role of mast cells in antiviral defense mechanisms and inflammatory reactions is discussed.

scholarly journals Mosquito antiviral defense mechanisms: a delicate balance between innate immunity and persistent viral infection

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Wai-Suet Lee ◽  
Julie A. Webster ◽  
Eugene T. Madzokere ◽  
Eloise B. Stephenson ◽  
Lara J. Herrero
Keyword(s):  
Innate Immunity ◽  
Viral Infection ◽  
Defense Mechanisms ◽  
Antiviral Defense ◽  
Persistent Viral Infection ◽  
Delicate Balance

scholarly journals Antiviral defense mechanisms in honey bees

2015 ◽  
Vol 10 ◽  
pp. 71-82 ◽  
Author(s):  
Laura M Brutscher ◽  
Katie F Daughenbaugh ◽  
Michelle L Flenniken
Keyword(s):  
Honey Bees ◽  
Defense Mechanisms ◽  
Antiviral Defense

scholarly journals The heat shock transcription factor HSF-1 protects Caenorhabditis elegans from peroxide stress

2020 ◽  
Author(s):  
Francesco A. Servello ◽  
Javier Apfeld
Keyword(s):  
Oxidative Stress ◽  
Transcription Factor ◽  
Caenorhabditis Elegans ◽  
Heat Shock ◽  
Defense Mechanisms ◽  
Heat Shock Transcription Factor ◽  
Transactivation Domain ◽  
C Elegans ◽  
Multicellular Organisms ◽  
Mild Temperature

AbstractCells induce conserved defense mechanisms that protect them from oxidative stress. How these defenses are regulated in multicellular organisms is incompletely understood. Using the nematode Caenorhabditis elegans, we show that the heat shock transcription factor HSF-1 protects the nematode from the oxidative stress induced by environmental peroxide. In response to a heat shock or a mild temperature increase, HSF-1 protects the nematodes from subsequent oxidative stress in a manner that depends on HSF-1’s transactivation domain. At constant temperature, HSF-1 protects the nematodes from oxidative stress independently of its transactivation domain, likely by inducing the expression of asp-4/cathepsin D and dapk-1/dapk. Thus, two distinct HSF-1-dependent processes protect C. elegans from oxidative stress.

scholarly journals Viral Activation of Interleukin-15 (IL-15): Characterization of a Virus-Inducible Element in the IL-15 Promoter Region

2000 ◽  
Vol 74 (16) ◽  
pp. 7338-7348 ◽  
Author(s):  
Nazli Azimi ◽  
Yutaka Tagaya ◽  
Jennifer Mariner ◽  
Thomas A. Waldmann
Keyword(s):  
Transcription Initiation ◽  
Defense Mechanisms ◽  
Initiation Site ◽  
Interferon Regulatory Factor ◽  
Antiviral Defense ◽  
Regulatory Factor ◽  
Mrna And Protein Expression ◽  
Interleukin 15 ◽  
Expression Plasmids

ABSTRACT We identified an interferon regulatory factor motif (IRF-E) upstream of an NF-κB binding site in the interleukin-15 (IL-15) promoter. Since these two motifs are part of the virus-inducible enhancer region of the beta interferon promoter, we speculated that there might be similar responses of these two genes to stimuli such as viruses. To test this hypothesis, L929 cells were infected with Newcastle disease virus (NDV), which led to the induction of IL-15 mRNA and protein expression. Using IL-15 promoter-reporter deletion constructs, a virus-inducible region, encompassing IRF-E, NF-κB, and a 13-nucleotide sequence flanked by these two motifs, was mapped to the −295-to-−243 position relative to the transcription initiation site. Using cotransfection studies, it was demonstrated that all three motifs were essential to achieve the maximum promoter activity induced by IRF-1 and NF-κB expression plasmids. The presence of a virus-inducible region in the IL-15 promoter suggests a role for IL-15 as a component of host antiviral defense mechanisms.

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