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Signaling pathways allow cells to detect and respond to a wide variety of chemical (e.g. Ca 2+ or chemokine proteins) and physical stimuli (e.g., sheer stress, light). Together, these pathways form an extensive communication network that regulates basic cell activities and coordinates the function of multiple cells or tissues. The process of cell signaling imposes many demands on the proteins that comprise these pathways, including the abilities to form active and inactive states, and to engage in multiple protein interactions. Furthermore, successful signaling often requires amplifying the signal, regulating or tuning the response to the signal, combining information sourced from multiple pathways, all while ensuring fidelity of the process. This sensitivity, adaptability, and tunability are possible, in part, due to the inclusion of intrinsically disordered regions in many proteins involved in cell signaling. The goal of this collection is to highlight the many roles of intrinsic disorder in cell signaling. Following an overview of resources that can be used to study intrinsically disordered proteins, this review highlights the critical role of intrinsically disordered proteins for signaling in widely diverse organisms (animals, plants, bacteria, fungi), in every category of cell signaling pathway (autocrine, juxtacrine, intracrine, paracrine, and endocrine) and at each stage (ligand, receptor, transducer, effector, terminator) in the cell signaling process. Thus, a cell signaling pathway cannot be fully described without understanding how intrinsically disordered protein regions contribute to its function. The ubiquitous presence of intrinsic disorder in different stages of diverse cell signaling pathways suggest that more mechanisms by which disorder modulates intra- and inter-cell signals remain to be discovered. Graphical abstract

Anthocyanins are a family of water-soluble vacuolar pigments present in almost all flowering plants. The chemistry, biosynthesis and functions of these flavonoids have been intensively studied, in part due to their benefit for human health. Given that they are efficient antioxidants, intense research has been devoted to studying their possible roles against damage caused by reactive oxygen species (ROS). However, the redox homeostasis established between antioxidants and ROS is important for plant growth and development. On the one hand, high levels of ROS can damage DNA, proteins, and lipids, on the other, they are also required for cell signaling, plant development and stress responses. Thus, a balance is needed in which antioxidants can remove excessive ROS, while not precluding ROS from triggering important cellular signaling cascades. In this article, we discuss how anthocyanins and ROS interact and how a deeper understanding of the balance between them could help improve plant productivity, nutritional value, and resistance to stress, while simultaneously maintaining proper cellular function and plant growth.Key messageThe balance between anthocyanins and ROS could be manipulated to improve plant productivity, nutritional value, and resistance to stress.

Gap junction channels mediate intercellular signalling that is crucial in tissue development, homeostasis and pathologic states such as cardiac arrhythmias, cancer and trauma. To explore the mechanism by which Ca 2+ blocks intercellular communication during tissue injury, we determined the X-ray crystal structures of the human Cx26 gap junction channel with and without bound Ca 2+ . The two structures were nearly identical, ruling out both a large-scale structural change and a local steric constriction of the pore. Ca 2+ coordination sites reside at the interfaces between adjacent subunits, near the entrance to the extracellular gap, where local, side chain conformational rearrangements enable Ca 2+ chelation. Computational analysis revealed that Ca 2+ -binding generates a positive electrostatic barrier that substantially inhibits permeation of cations such as K + into the pore. Our results provide structural evidence for a unique mechanism of channel regulation: ionic conduction block via an electrostatic barrier rather than steric occlusion of the channel pore. Intercellular signalling can be mediated by gap junction channels, and calcium blocks this signally during tissue injury. Here, the authors use X-ray crystallography and molecular dynamics to show that the calcium forms an electrostatic barrier to prevent transport of cations.

Triggering receptor expressed on myeloid cells 1 (TREM‐1) is critically involved in the pathogenesis of rheumatoid arthritis (RA). In contrast to cytokine blockers, therapeutic blockade of TREM‐1 can blunt excessive inflammation while preserving the capacity for microbial control. However, the nature of the TREM‐1 ligand(s) and mechanisms of TREM‐1 signalling are still not yet well understood, impeding the development of clinically relevant inhibitors of TREM‐1. The aim of this study was to evaluate the anti‐arthritic activity of a novel, ligand‐independent TREM‐1 inhibitory nonapeptide GF9 that was rationally designed using the signalling chain homo oligomerization (SCHOOL) model of cell signalling. Free GF9 and GF9 bound to macrophage‐targeted nanoparticles that mimic human high‐density lipoproteins (GF9‐HDL) were used to treat collagen‐induced arthritis (CIA). We also tested if 31‐mer peptides with sequences from GF9 and helices 4 (GE31) and 6 (GA31) of the major HDL protein, apolipoprotein A‐I, are able to perform three functions: assist in the self‐assembly of GA/E31‐HDL, target these particles to macrophages and block TREM‐1 signalling. We showed that GF9, but not control peptide, ameliorated CIA and protected against bone and cartilage damage. The therapeutic effect of GF9 was accompanied by a reduction in the plasma levels of macrophage colony‐stimulating factor and pro‐inflammatory cytokines such as tumour necrosis factor‐α, interleukin (IL)‐1 and IL‐6. Incorporation of GF9 alone or as a part of GE31 and GA31 peptides into HDL significantly increased its therapeutic efficacy. Collectively, our findings suggest that TREM‐1 inhibitory SCHOOL sequences may be promising alternatives for the treatment of RA.

Heavy metal concentrations exceeding permissible limits threaten human life, plant life, and all other life forms. Different natural and anthropogenic activities emit toxic heavy metals in the soil, air, and water. Plants consume toxic heavy metals from their roots and foliar part inside the plant. Heavy metals may interfere with various aspects of the plants, such as biochemistry, bio-molecules, and physiological processes, which usually translate into morphological and anatomical changes. They use various strategies to deal with the toxic effects of heavy metal contamination. Some of these strategies include restricting heavy metals to the cell wall, vascular sequestration, and synthesis of various biochemical compounds, such as phyto-chelators and organic acids, to bind the free moving heavy metal ions so that the toxic effects are minimized. This review focuses on several aspects of genetics, molecular, and cell signaling levels, which integrate to produce a coordinated response to heavy metal toxicity and interpret the exact strategies behind the tolerance of heavy metals stress. It is suggested that various aspects of some model plant species must be thoroughly studied to comprehend the approaches of heavy metal tolerance to put that knowledge into practical use.

Signalling activities are tightly regulated to control cellular responses. Heparan sulfate proteoglycans (HSPGs) at the cell membrane and extracellular matrix regulate ligand availability and interaction with a range of key receptors. SULF1 and SULF2 enzymes modify HSPG sulfation by removing 6-O sulfates to regulate cell signalling but are considered functionally identical. Our in vitro mRNA and protein analyses of two diverse human endothelial cell lines, however, highlight their markedly distinct regulatory roles of maintaining specific HSPG sulfation patterns through feedback regulation of HS 6-O transferase (HS6ST) activities and highly divergent roles in vascular endothelial growth factor (VEGF) and Transforming growth factor β (TGFβ) cell signalling activities. Unlike Sulf2, Sulf1 over-expression in dermal microvascular HMec1 cells promotes TGFβ and VEGF cell signalling by simultaneously upregulating HS6ST1 activity. In contrast, Sulf1 over-expression in venous ea926 cells has the opposite effect as it attenuates both TGFβ and VEGF signalling while Sulf2 over-expression maintains the control phenotype. Exposure of these cells to VEGF-A, TGFβ1, and their inhibitors further highlights their endothelial cell type-specific responses and integral growth factor interactions to regulate cell signalling and selective feedback regulation of HSPG sulfation that additionally exploits alternative Sulf2 RNA-splicing to regulate net VEGF-A and TGFβ cell signalling activities.

Microbial cells do not live in isolation in their environment, but rather they communicate with each other using chemical signals. This sophisticated mode of cell-to-cell signalling, known as quorum sensing, was first discovered in bacteria, and coordinates the behaviour of microbial population behaviour in a cell-density-dependent manner. More recently, these mechanisms have been described in eukaryotes, particularly in fungi, where they regulate processes such as pathogenesis, morphological differentiation, secondary metabolite production and biofilm formation. In this manuscript, we review the information available to date on these processes in yeast, dimorphic fungi and filamentous fungi. We analyse the diverse chemical 'languages' used by different groups of fungi, their possible cross-talk and interkingdom interactions with other organisms. We discuss the existence of these mechanisms in multicellular organisms, the ecophysiological role of QS in fungal colonisation and the potential applications of these mechanisms in biotechnology and pathogenesis.

We recently reported on CFP-Epac-YFP, an Epac-based single polypeptide FRET reporter to resolve cAMP levels in living cells. In this study, we compared and optimized the fluorescent protein donor/acceptor pairs for use in biosensors such as CFP-Epac-YFP. Our strategy was to prepare a wide range of constructs consisting of different donor and acceptor fluorescent proteins separated by a short linker. Constructs were expressed in HEK293 cells and tested for FRET and other relevant properties. The most promising pairs were subsequently used in an attempt to improve the FRET span of the Epac-based cAMP sensor. The results show significant albeit not perfect correlation between performance in the spacer construct and in the Epac sensor. Finally, this strategy enabled us to identify improved sensors both for detection by sensitized emission and by fluorescent lifetime imaging. The present overview should be helpful in guiding development of future FRET sensors.

There is growing awareness that tumour cells build up a \"self-advantageous\" microenvironment that reduces effectiveness of anti-tumour immune response. While many different immunosuppressive mechanisms are likely to come into play, recent evidence suggests that extracellular adenosine acting at A2A receptors may have a major role in down-modulating the immune response as cancerous tissues contain elevated levels of adenosine and adenosine break-down products. While there is no doubt that all cells possess plasma membrane adenosine transporters that mediate adenosine uptake and may also allow its release, it is now clear that most of extracellularly-generated adenosine originates from the catabolism of extracellular ATP. Measurement of extracellular ATP is generally performed in cell supernatants by HPLC or soluble luciferin-luciferase assay, thus it generally turns out to be laborious and inaccurate. We have engineered a chimeric plasma membrane-targeted luciferase that allows in vivo real-time imaging of extracellular ATP. With this novel probe we have measured the ATP concentration within the tumour microenvironment of several experimentally-induced tumours. Our results show that ATP in the tumour interstitium is in the hundreds micromolar range, while it is basically undetectable in healthy tissues. Here we show that a chimeric plasma membrane-targeted luciferase allows in vivo detection of high extracellular ATP concentration at tumour sites. On the contrary, tumour-free tissues show undetectable extracellular ATP levels. Extracellular ATP may be crucial for the tumour not only as a stimulus for growth but also as a source of an immunosuppressive agent such as adenosine. Our approach offers a new tool for the investigation of the biochemical composition of tumour milieu and for development of novel therapies based on the modulation of extracellular purine-based signalling.

Animal models are an integral part of the drug development and evaluation process. However, they are unsurprisingly imperfect reflections of humans, and the extent and nature of many immunological differences are unknown. With the rise of targeted and biological therapeutics, it is increasingly important that we understand the molecular differences in the immunological behavior of humans and model organisms. However, very few antibodies are raised against non-human primate antigens, and databases of cross-reactivity between species are incomplete. Thus, we screened 332 antibodies in five immune cell populations in blood from humans and four non-human primate species generating a comprehensive cross-reactivity catalog that includes cell type-specificity. We used this catalog to create large mass cytometry universal cross-species phenotyping and signaling panels for humans, along with three of the model organisms most similar to humans: rhesus and cynomolgus macaques and African green monkeys; and one of the mammalian models most widely used in drug development: C57BL/6 mice. As a proof-of-principle, we measured immune cell signaling responses across all five species to an array of 15 stimuli using mass cytometry. We found numerous instances of different cellular phenotypes and immune signaling events occurring within and between species, and detailed three examples (double-positive T cell frequency and signaling; granulocyte response to Bacillus anthracis antigen; and B cell subsets). We also explore the correlation of herpes simian B virus serostatus on the immune profile. Antibody panels and the full dataset generated are available online as a resource to enable future studies comparing immune responses across species during the evaluation of therapeutics.