Besides its role as the blueprint of life, DNA can also alert the cell to the presence of microbial pathogens as well as damaged or malignant cells. A major sensor of DNA that triggers the innate ...immune response is cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) (cGAMP) synthase (cGAS), which produces the second messenger cGAMP. cGAMP activates stimulator of interferon genes (STING), which activates a signaling cascade leading to the production of type I interferons and other immune mediators. Recent research has demonstrated an expanding role of the cGAS-cGAMP-STING pathway in many physiological and pathological processes, including host defense against microbial infections, anti-tumor immunity, cellular senescence, autophagy, and autoimmune and inflammatory diseases. Biochemical and structural studies have elucidated the mechanism of signal transduction in the cGAS pathway at the atomic resolution. This review focuses on the structural and mechanistic insights into the roles of cGAS and STING in immunity and diseases revealed by these recent studies.
The cGAS-STING pathway mediates innate immune responses to pathogenic DNA from microbes or damaged cells. In this review, Zhang et al. focus on recent biochemical and structural studies of key proteins in the cGAS-STING pathway that provide mechanistic insights into immunity and diseases.
There exists a bidirectional communication system between the gastrointestinal tract and the brain. Increasing evidence shows that gut microbiota can play a critical role in this communication; thus, ...the concept of a gut microbiota and brain axis is emerging. Here, we review recent findings in the relationship between intestinal microbes and brain function, such as anxiety, depression, stress, autism, learning, and memory. We highlight the advances in modulating brain development and behavior by probiotics, prebiotics, and diet through the gut microbiota-brain axis. A variety of mechanisms including immune, neural, and metabolic pathways may be involved in modulation of the gut microbiota-brain axis. We also discuss some future challenges. A deeper understanding of the relationship between the gut bacteria and their hosts is implicated in developing microbial-based therapeutic strategies for brain disorders.
Infections by pathogens that contain DNA trigger the production of type-I interferons and inflammatory cytokines through cyclic GMP-AMP synthase, which produces 2'3'-cyclic GMP-AMP (cGAMP) that binds ...to and activates stimulator of interferon genes (STING; also known as TMEM173, MITA, ERIS and MPYS)
. STING is an endoplasmic-reticulum membrane protein that contains four transmembrane helices followed by a cytoplasmic ligand-binding and signalling domain
. The cytoplasmic domain of STING forms a dimer, which undergoes a conformational change upon binding to cGAMP
. However, it remains unclear how this conformational change leads to STING activation. Here we present cryo-electron microscopy structures of full-length STING from human and chicken in the inactive dimeric state (about 80 kDa in size), as well as cGAMP-bound chicken STING in both the dimeric and tetrameric states. The structures show that the transmembrane and cytoplasmic regions interact to form an integrated, domain-swapped dimeric assembly. Closure of the ligand-binding domain, induced by cGAMP, leads to a 180° rotation of the ligand-binding domain relative to the transmembrane domain. This rotation is coupled to a conformational change in a loop on the side of the ligand-binding-domain dimer, which leads to the formation of the STING tetramer and higher-order oligomers through side-by-side packing. This model of STING oligomerization and activation is supported by our structure-based mutational analyses.
Lentinula edodes-derived polysaccharides possess many therapeutic characteristics, including anti-tumor and immuno-modulation. The gut microbes play a critical role in modulation of immune function. ...However, the impact of Lentinula edodes-derived polysaccharides on the gut microbes have not yet been explored. In this study, high-throughput pyrosequencing technique was employed to investigate the effects of a new heteropolysaccharide L2 from Lentinula edodes on microbiota diversity and composition of small intestine, cecum, colon and distal end of colon (feces) in mice. The results demonstrated that along mouse intestine the microbiota exhibit distinctly different space distribution. L2 treatment reduced the diversity and evenness of gut microbiota along the intestine, especially in the cecum and colon. In the fecal microbial communities, the decrease of Bacteroidetes by significantly increasing Proteobacteria were observed, which were characterized by the increased Helicobacteraceae and reduced S24-7 at family level. Some OTUs, corresponding to Bacteroides acidifaciens, Alistipes and Helicobacter suncus, were found to be significantly increased in L2 treated-mice. In particular, 4 phyla Chloroflexi, Gemmatimonadetes, Nitrospirae and Planctomycetes are exclusively present in L2-treated mice. This is helpful for further demonstrating healthy action mechanism of Lentinula edodes-derived polysaccharide L2.
The presence of microbial or self DNA in the cytoplasm of mammalian cells is a danger signal detected by the DNA sensor cyclic-GMP-AMP (cGAMP) synthase (cGAS), which catalyzes the production of cGAMP ...that in turn serves as a second messenger to activate innate immune responses. Here we show that endogenous cGAMP in mammalian cells contains two distinct phosphodiester linkages, one between 2′-OH of GMP and 5′-phosphate of AMP, and the other between 3′-OH of AMP and 5′-phosphate of GMP. This molecule, termed 2′3′-cGAMP, is unique in that it binds to the adaptor protein STING with a much greater affinity than cGAMP molecules containing other combinations of phosphodiester linkages. The crystal structure of STING bound to 2′3′-cGAMP revealed the structural basis of this high-affinity binding and a ligand-induced conformational change in STING that may underlie its activation.
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•2′3′-cGAMP is an endogenous second messenger produced by mammalian cells•2′3′-cGAMP is a high-affinity ligand for STING•2′3′-cGAMP is a potent inducer of type I interferons•2′3′-cGAMP binding induces conformational changes of STING
Inhibitory effects of the identified peptides (RR, LR and GK) and drug Sitaglipin.
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•Spirulina platensis protein had anti-diabetes activities in IR cell model.•Anti-diabetes peptides ...were identified from S. platensis for the first time.•11 anti-diabetes peptides were identified from S. platensis protein.•LRSELAAWSR displayed the best activities on and DPP-IV.
In this study, ultrasound coupled with subcritical water (USW) technology was employed to extract S. platensis protein, and its inhibitory effect on three enzymes (α-amylase, α-glucosidase and dipeptidyl peptidase-4 (DPP-IV)) was evaluated. Subsequently, using insulin resistant-HepG2 cell model, the data presented that the USW-extracted protein significantly (p < 0.01) increased glycogen content, hexokinase and pyruvate kinase activities. Then, 11 peptides were identified from intact protein or the HPLC-separated protein fractions by LC-MS/MS. After in silico prediction, 3 peptides (GVPMPNK, RNPFVFAPTLLTVAAR and LRSELAAWSR) were synthesized, and their α-amylase, α-glucosidase and DPP-IV inhibition activities were validated. Among them, LRSELAAWSR displayed the medium activity on α-amylase (IC50 = 313.6 μg/mL), but the best activities on α-glucosidase (IC50 = 134.2 μg/mL) and DPP-IV (IC50 = 167.3 μg/mL). In summary, for the first time, anti-diabetes peptides were identified from Spirulina platensis, which are useful for functional food additives and pharmaceuticals against type 2 diabetes.
Stimulator of interferon genes (STING) is an adaptor protein in innate immunity against DNA viruses or bacteria
. STING-mediated immunity could be exploited in the development of vaccines or cancer ...immunotherapies. STING is a transmembrane dimeric protein that is located in the endoplasmic reticulum or in the Golgi apparatus. STING is activated by the binding of its cytoplasmic ligand-binding domain to cyclic dinucleotides that are produced by the DNA sensor cyclic GMP-AMP (cGAMP) synthase or by invading bacteria
. Cyclic dinucleotides induce a conformational change in the STING ligand-binding domain, which leads to a high-order oligomerization of STING that is essential for triggering the downstream signalling pathways
. However, the cGAMP-induced STING oligomers tend to dissociate in solution and have not been resolved to high resolution, which limits our understanding of the activation mechanism. Here we show that a small-molecule agonist, compound 53 (C53)
, promotes the oligomerization and activation of human STING through a mechanism orthogonal to that of cGAMP. We determined a cryo-electron microscopy structure of STING bound to both C53 and cGAMP, revealing a stable oligomer that is formed by side-by-side packing and has a curled overall shape. Notably, C53 binds to a cryptic pocket in the STING transmembrane domain, between the two subunits of the STING dimer. This binding triggers outward shifts of transmembrane helices in the dimer, and induces inter-dimer interactions between these helices to mediate the formation of the high-order oligomer. Our functional analyses show that cGAMP and C53 together induce stronger activation of STING than either ligand alone.
Biodiesel has received much attention in recent years. Although numerous reports are available on the production of biodiesel from vegetable oils of terraneous oil-plants, such as soybean, sunflower ...and palm oils, the production of biodiesel from microalgae is a newly emerging field. Microalgal biotechnology appears to possess high potential for biodiesel production because a significant increase in lipid content of microalgae is now possible through heterotrophic cultivation and genetic engineering approaches. This paper provides an overview of the technologies in the production of biodiesel from microalgae, including the various modes of cultivation for the production of oil-rich microalgal biomass, as well as the subsequent downstream processing for biodiesel production. The advances and prospects of using microalgal biotechnology for biodiesel production are discussed.
Within the parent protein molecule, most peptides are inactive, and they are released with biofunctionalities after enzymatic hydrolysis. Marine algae have high protein content, up to 47% of the dry ...weight, depending on the season and the species. Recently, there is an increasing interest in using marine algae protein as a source of bioactive peptides due to their health promotion and disease therapy potentials. This review presents an overview of marine algae-derived bioactive peptides and especially highlights some key issues, such as in silico proteolysis and quantitative structure–activity relationship studies, in vivo fate of bioactive peptides, and novel technologies in bioactive peptides studies and production.
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