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Inhibition of immune checkpoint molecules, PD‐1 and CTLA4, has been shown to be a promising cancer treatment. PD‐1 and CTLA4 inhibit TCR and co‐stimulatory signals. The third T cell activation signal represents the signals from the cytokine receptors. The cytokine interferon‐γ (IFNγ) plays an important role in anti‐tumor immunity by activating cytotoxic T cells (CTLs). Most cytokines use the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway, and the suppressors of cytokine signaling (SOCS) family of proteins are major negative regulators of the JAK/STAT pathway. Among SOCS proteins, CIS, SOCS1, and SOCS3 proteins can be considered the third immunocheckpoint molecules since they regulate cytokine signals that control the polarization of CD4+ T cells and the maturation of CD8+ T cells. This review summarizes recent progress on CIS, SOCS1, and SOCS3 in terms of their anti‐tumor immunity and potential applications. Inhibition of immune‐checkpoint molecules, PD‐1 and CTLA4, has been shown to be a promising cancer treatment. SOCS proteins are the third immune‐checkpoint molecules that inhibit cytokine signaling. This review is focusing on the mechanism of inhibition of cytokine signaling by CIS, SOCS1 and SOCS3, and their relationship to T cell biology and anti‐tumor immunity.

The SOCS family of proteins are negative-feedback inhibitors of signalling induced by cytokines that act via the JAK/STAT pathway. SOCS proteins can act as ubiquitin ligases by recruiting Cullin5 to ubiquitinate signalling components; however, SOCS1, the most potent member of the family, can also inhibit JAK directly. Here we determine the structural basis of both these modes of inhibition. Due to alterations within the SOCS box domain, SOCS1 has a compromised ability to recruit Cullin5; however, it is a direct, potent and selective inhibitor of JAK catalytic activity. The kinase inhibitory region of SOCS1 targets the substrate binding groove of JAK with high specificity and thereby blocks any subsequent phosphorylation. SOCS1 is a potent inhibitor of the interferon gamma (IFNγ) pathway, however, it does not bind the IFNγ receptor, making its mode-of-action distinct from SOCS3. These findings reveal the mechanism used by SOCS1 to inhibit signalling by inflammatory cytokines. Cytokines are key molecules in controlling haematopoiesis that signal via the JAK/STAT pathway. Here the authors present the structures of SOCS1 bound to its JAK1 target as well as in complex with elonginB and elonginC, providing a molecular explanation for the potent JAK- inhibitory activity of SOCS1.

ObjectivesAdult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disease; its management is largely empirical. This is the first clinical study to determine if interleukin (IL)-18 inhibition, using the recombinant human IL-18 binding protein, tadekinig alfa, is a therapeutic option in AOSD.MethodsIn this phase II, open-label study, patients were ≥18 years with active AOSD plus fever or C reactive protein (CRP) levels ≥10 mg/L despite treatment with prednisone and/or conventional synthetic disease-modifying antirheumatic drugs (DMARDs). Previous biological DMARD treatment was permitted. Patients received tadekinig alfa 80 mg or 160 mg subcutaneously three times per week for 12 weeks; those receiving 80 mg not achieving early predicted response criteria (reduction of ≥50% CRP values from baseline and fever resolution) were up-titrated to 160 mg for a further 12 weeks. The primary endpoint was the occurrence of adverse events (AEs) throughout the study.ResultsTen patients were assigned to receive 80 mg tadekinig alfa and 13 patients to the 160 mg dose. One hundred and fifty-five treatment-emerging AEs were recorded, and 47 were considered related to the study drug. Most AEs were mild and resolved after drug discontinuation. Three serious AEs occurred, one possibly related to treatment (toxic optic neuropathy). At week 3, 5 of 10 patients receiving 80 mg and 6 of 12 patients receiving 160 mg achieved the predefined response criteria.ConclusionsOur results indicate that tadekinig alfa appears to have a favourable safety profile and is associated with early signs of efficacy in patients with AOSD.Trial registration numberNCT02398435.

The Hippo signalling pathway has emerged as a key regulator of organ size, tissue homeostasis, and patterning. Recent studies have shown that two effectors in this pathway, YAP/TAZ, modulate Wnt/β‐catenin signalling through their interaction with β‐catenin or Dishevelled, depending on biological contexts. Here, we identify a novel mechanism through which Hippo signalling inhibits Wnt/β‐catenin signalling. We show that YAP and TAZ, the transcriptional co‐activators in the Hippo pathway, suppress Wnt signalling without suppressing the stability of β‐catenin but through preventing its nuclear translocation. Our results show that YAP/TAZ binds to β‐catenin, thereby suppressing Wnt‐target gene expression, and that the Hippo pathway‐stimulated phosphorylation of YAP, which induces cytoplasmic translocation of YAP, is required for the YAP‐mediated inhibition of Wnt/β‐catenin signalling. We also find that downregulation of Hippo signalling correlates with upregulation of β‐catenin signalling in colorectal cancers. Remarkably, our analysis demonstrates that phosphorylated YAP suppresses nuclear translocation of β‐catenin by directly binding to it in the cytoplasm. These results provide a novel mechanism, in which Hippo signalling antagonizes Wnt signalling by regulating nuclear translocation of β‐catenin. The Hippo pathway effector YAZ is found to bind β‐catenin and prevents its nuclear translocation. The resulting downregulation of Wnt signal transduction provides a new example for intersection of Hippo and Wnt signalling, two key regulatory pathways in animal development

Calcium (Ca ) is an essential signaling molecule that controls a wide range of biological functions. In the immune system, calcium signals play a central role in a variety of cellular functions such as proliferation, differentiation, apoptosis, and numerous gene transcriptions. During an immune response, the engagement of T-cell and B-cell antigen receptors induces a decrease in the intracellular Ca store and then activates store-operated Ca entry (SOCE) to raise the intracellular Ca concentration, which is mediated by the Ca release-activated Ca (CRAC) channels. Recently, identification of the two critical regulators of the CRAC channel, stromal interaction molecule (STIM) and Orai1, has broadened our understanding of the regulatory mechanisms of Ca signaling in lymphocytes. Repetitive or prolonged increase in intracellular Ca is required for the calcineurin-mediated dephosphorylation of the nuclear factor of an activated T cell (NFAT). Recent data indicate that Ca -calcineurin-NFAT1 to 4 pathways are dysregulated in autoimmune diseases. Therefore, calcineurin inhibitors, cyclosporine and tacrolimus, have been used for the treatment of such autoimmune diseases as systemic lupus erythematosus and rheumatoid arthritis. Here, we review the role of the Ca -calcineurin-NFAT signaling pathway in health and diseases, focusing on the STIM and Orai1, and discuss the deregulated calcium-mediated calcineurin-NFAT pathway in autoimmune diseases.

• Diatoms are globally important phytoplankton that dominate coastal and polar-ice assemblages. These environments exhibit substantial changes in salinity over dynamic spatiotemporal regimes. Rapid sensory systems are vital to mitigate the harmful consequences of osmotic stress. Population-based analyses have suggested that Ca2+ signalling is involved in diatom osmotic sensing. However, mechanistic insight of the role of osmotic Ca2+ signalling is limited. • Here, we show that Phaeodactylum Ca2+ elevations are essential for surviving hypo-osmotic shock. Moreover, employing novel single-cell imaging techniques we have characterised real-time Ca2+ signalling responses in single diatom cells to environmental osmotic perturbations. • We observe that intracellular spatiotemporal patterns of osmotic-induced Ca2+ elevations encode vital information regarding the nature of the osmotic stimulus. Localised Ca2+ signals evoked by mild or gradual hypo-osmotic shocks are propagated globally from the apical cell tips, enabling fine-tuned cell volume regulation across the whole cell. • Finally, we demonstrate that diatoms adopt Ca2+-independent and dependent mechanisms for osmoregulation. We find that efflux of organic osmolytes occurs in a Ca2+-independent manner, but this response is insufficient to mitigate cell damage during hypo-osmotic shock. By comparison, Ca2+-dependent signalling is necessary to prevent cell bursting via precise coordination of K⁺ transport, and therefore is likely to underpin survival in dynamic osmotic environments.

Lack or loss of tumor antigenicity represents one of the key mechanisms of immune escape and resistance to T cell–based immunotherapies. Evidence suggests that activation of stimulator of interferon genes (STING) signaling in tumor cells can augment their antigenicity by triggering a type I IFN-mediated sequence of autocrine and paracrine events. Although suppression of this pathway in melanoma and other tumor types has been consistently reported, the mechanistic basis remains unclear. In this study, we asked whether this suppression is, in part, epigenetically regulated and whether it is indeed a driver of melanoma resistance to T cell–based immunotherapies. Using genome-wide DNA methylation profiling, we show that promoter hypermethylation of cGAS and STING genes mediates their coordinated transcriptional silencing and contributes to the widespread impairment of the STING signaling function in clinically-relevant human melanomas and melanoma cell lines. This suppression is reversible through pharmacologic inhibition of DNA methylation, which can reinstate functional STING signaling in at least half of the examined cell lines. Using a series of T cell recognition assays with HLA-matched human melanoma tumor-infiltrating lymphocytes (TIL), we further show that demethylation-mediated restoration of STING signaling in STING-defective melanoma cell lines can improve their antigenicity through the up-regulation of MHC class I molecules and thereby enhance their recognition and killing by cytotoxic T cells. These findings not only elucidate the contribution of epigenetic processes and specifically DNA methylation in melanoma-intrinsic STING signaling impairment but also highlight their functional significance in mediating tumor-immune evasion and resistance to T cell–based immunotherapies.

Unlike in animals, sperm in flowering plants are immotile and they are embraced as passive cargoes by a pollen tube which embarks on a long journey in the pistil to deliver them to the female gametophyte for fertilization. How the pollen tube switches from a rapid polarized growth towards its target to an abrupt disintegration for sperm cell release inside the female gametophyte is puzzling. Recent studies have shown that members of the Catharanthus roseus RLK1-like (CrRLK1L) receptor kinase family and their ligands, 5-kDa cysteine-rich peptide rapid alkalinization factors (RALFs), engage in an intricate balancing act involving autocrine and paracrine signaling to maintain pollen tube growth and induce timely tube rupture at the spatially confined pollen tube–female gametophyte interface. Here, we review recent progress related to pollen tube integrity control, mainly focusing on the molecular understanding of signaling as well as intracellular signaling nodes in Arabidopsis. Some missing links and future perspectives are also discussed.

Molecular knowledge of biological processes is a cornerstone in omics data analysis. Applied to single‐cell data, such analyses provide mechanistic insights into individual cells and their interactions. However, knowledge of intercellular communication is scarce, scattered across resources, and not linked to intracellular processes. To address this gap, we combined over 100 resources covering interactions and roles of proteins in inter‐ and intracellular signaling, as well as transcriptional and post‐transcriptional regulation. We added protein complex information and annotations on function, localization, and role in diseases for each protein. The resource is available for human, and via homology translation for mouse and rat. The data are accessible via OmniPath ’s web service ( https://omnipathdb.org/ ), a Cytoscape plug‐in, and packages in R/Bioconductor and Python, providing access options for computational and experimental scientists. We created workflows with tutorials to facilitate the analysis of cell–cell interactions and affected downstream intracellular signaling processes. OmniPath provides a single access point to knowledge spanning intra‐ and intercellular processes for data analysis, as we demonstrate in applications studying SARS‐CoV‐2 infection and ulcerative colitis. SYNOPSIS Over 100 resources are integrated into OmniPath , a comprehensive knowledge base of intra‐ and inter‐cellular signaling. Workflows are provided and illustrated in case studies analyzing omics data in SARS‐CoV‐2 infection and ulcerative colitis. OmniPath includes 4,000,000 annotations for over 20,000 proteins. A new framework defining transmitter and receiver roles generalizes the concepts of ligand and receptor . Integrated analysis of intra‐ and intercellular signaling can be performed to study how cells affect each other in healthy and diseased conditions. Software tools and workflows in R and Python facilitate the analysis of bulk and single‐cell omics data using tools such as CellPhoneDB , NicheNet and CARNIVAL . Graphical Abstract Over 100 resources are integrated into OmniPath , a comprehensive knowledge base of intra‐ and inter‐cellular signaling. Workflows are provided and illustrated in case studies analyzing omics data in SARS‐CoV‐2 infection and ulcerative colitis.

The production of reactive oxygen species (ROS) is the unavoidable consequence of aerobic life. ROS is a collective term that includes both oxygen radicals, like superoxide ( O 2 . − ) and hydroxyl (·OH) radicals, and other non-radicals such as hydrogen peroxide (H₂O₂), singlet oxygen (¹O₂ or ¹Δg), etc. In plants, ROS are produced in different cell compartments and are oxidizing species, particularly hydroxyl radicals and singlet oxygen, that can produce serious damage in biological systems (oxidative stress). However, plant cells also have an array of antioxidants which, normally, can scavenge the excess oxidants produced and so avoid deleterious effects on the plant cell bio-molecules. The concept of ‘oxidative stress’ was re-evaluated in recent years and the term ‘oxidative signalling’ was created. This means that ROS production, apart from being a potentially harmful process, is also an important component of the signalling network that plants use for their development and for responding to environmental challenges. It is known that ROS play an important role regulating numerous biological processes such as growth, development, response to biotic and environmental stresses, and programmed cell death. The term reactive nitrogen species (RNS) includes radicals like nitric oxide (NO·) and nitric dioxide (NO₂·), as well as non-radicals such as nitrous acid (HNO₂) and dinitrogen tetroxide (N₂O₄), among others. RNS are also produced in plants although the generating systems have still not been fully characterized. Nitric oxide (NO·) has an important function as a key signalling molecule in plant growth, development, and senescence, and RNS, like ROS, also play an important role as signalling molecules in the response to environmental (abiotic) stress. Similarly, NO· is a key mediator, in co-operation with ROS, in the defence response to pathogen attacks in plants. ROS and RNS have been demonstrated to have an increasingly important role in biology and medicine.