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https://www.readbyqxmd.com/read/28625530/the-emerging-roles-of-sting-in-bacterial-infections
#1
REVIEW
Fabio V Marinho, Sulayman Benmerzoug, Sergio C Oliveira, Bernhard Ryffel, V F J Quesniaux
The STING (Stimulator of Interferon Genes) protein connects microorganism cytosolic sensing with effector functions of the host cell by sensing directly cyclic dinucleotides (CDNs), originating from pathogens or from the host upon DNA recognition. Although STING activation favors effective immune responses against viral infections, its role during bacterial diseases is controversial, ranging from protective to detrimental effects for the host. In this review, we summarize important features of the STING activation pathway and recent highlights about the role of STING in bacterial infections by Chlamydia, Listeria, Francisella, Brucella, Shigella, Salmonella, Streptococcus, and Neisseria genera, with a special focus on mycobacteria...
June 15, 2017: Trends in Microbiology
https://www.readbyqxmd.com/read/28624218/targeted-multifunctional-lipid-eco-plasmid-dna-nanoparticles-as-efficient-non-viral-gene-therapy-for-leber-s-congenital-amaurosis
#2
Da Sun, Bhubanananda Sahu, Songqi Gao, Rebecca M Schur, Amita M Vaidya, Akiko Maeda, Krzysztof Palczewski, Zheng-Rong Lu
Development of a gene delivery system with high efficiency and a good safety profile is essential for successful gene therapy. Here we developed a targeted non-viral delivery system using a multifunctional lipid ECO for treating Leber's congenital amaurosis type 2 (LCA2) and tested this in a mouse model. ECO formed stable nanoparticles with plasmid DNA (pDNA) at a low amine to phosphate (N/P) ratio and mediated high gene transfection efficiency in ARPE-19 cells because of their intrinsic properties of pH-sensitive amphiphilic endosomal escape and reductive cytosolic release (PERC)...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28620207/dengue-virus-activates-cgas-through-the-release-of-mitochondrial-dna
#3
Bo Sun, Karin B Sundström, Jun Jie Chew, Pradeep Bist, Esther S Gan, Hwee Cheng Tan, Kenneth C Goh, Tanu Chawla, Choon Kit Tang, Eng Eong Ooi
Cyclic GMP-AMP synthetase (cGAS) is a DNA-specific cytosolic sensor, which detects and initiates host defense responses against microbial DNA. It is thus curious that a recent study identified cGAS as playing important roles in inhibiting positive-sense single-stranded RNA (+ssRNA) viral infection, especially since RNA is not known to activate cGAS. Using a dengue virus serotype 2 (DENV-2) vaccine strain (PDK53), we show that infection creates an endogenous source of cytosolic DNA in infected cells through the release of mitochondrial DNA (mtDNA) to drive the production of cGAMP by cGAS...
June 15, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28614305/bap1-regulates-ip3r3-mediated-ca-2-flux-to-mitochondria-suppressing-cell-transformation
#4
Angela Bononi, Carlotta Giorgi, Simone Patergnani, David Larson, Kaitlyn Verbruggen, Mika Tanji, Laura Pellegrini, Valentina Signorato, Federica Olivetto, Sandra Pastorino, Masaki Nasu, Andrea Napolitano, Giovanni Gaudino, Paul Morris, Greg Sakamoto, Laura K Ferris, Alberto Danese, Andrea Raimondi, Carlo Tacchetti, Shafi Kuchay, Harvey I Pass, El Bachir Affar, Haining Yang, Paolo Pinton, Michele Carbone
BRCA1-associated protein 1 (BAP1) is a potent tumour suppressor gene that modulates environmental carcinogenesis. All carriers of inherited heterozygous germline BAP1-inactivating mutations (BAP1(+/-)) developed one and often several BAP1(-/-) malignancies in their lifetime, mostly malignant mesothelioma, uveal melanoma, and so on. Moreover, BAP1-acquired biallelic mutations are frequent in human cancers. BAP1 tumour suppressor activity has been attributed to its nuclear localization, where it helps to maintain genome integrity...
June 14, 2017: Nature
https://www.readbyqxmd.com/read/28611389/nuclear-tradd-prevents-dna-damage-mediated-death-by-facilitating-non-homologous-end-joining-repair
#5
Gi-Bang Koo, Jae-Hoon Ji, Hyeseong Cho, Michael J Morgan, You-Sun Kim
TNF receptor-associated death domain (TRADD) is an essential mediator of TNF receptor signaling, and serves as an adaptor to recruit other effectors. TRADD has been shown to cycle between the cytoplasm and nucleus due to its nuclear localization (NLS) and export sequences (NES). However, the underlying function of nuclear TRADD is poorly understood. Here we demonstrate that cytoplasmic TRADD translocates to DNA double-strand break sites (DSBs) during the DNA damage response (DDR). Deficiency of TRADD or its sequestration in cytosol leads to accumulation of γH2AX-positive foci in response to DNA damage, which is reversed by nuclear TRADD expression...
June 13, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28605379/voltage-clamp-fluorometry-in-xenopus-oocytes-using-fluorescent-unnatural-amino-acids
#6
Tanja Kalstrup, Rikard Blunck
Voltage-Clamp Fluorometry (VCF) has been the technique of choice to investigate the structure and function of electrogenic membrane proteins where real-time measurements of fluorescence and currents simultaneously report on local rearrangements and global function, respectively(1). While high-resolution structural techniques such as cryo-electron microscopy or X-ray crystallography provide static images of the proteins of interest, VCF provides dynamic structural data that allows us to link the structural rearrangements (fluorescence) to dynamic functional data (electrophysiology)...
May 27, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28598415/dna-exonuclease-trex1-regulates-radiotherapy-induced-tumour-immunogenicity
#7
Claire Vanpouille-Box, Amandine Alard, Molykutty J Aryankalayil, Yasmeen Sarfraz, Julie M Diamond, Robert J Schneider, Giorgio Inghirami, C Norman Coleman, Silvia C Formenti, Sandra Demaria
Radiotherapy is under investigation for its ability to enhance responses to immunotherapy. However, the mechanisms by which radiation induces anti-tumour T cells remain unclear. We show that the DNA exonuclease Trex1 is induced by radiation doses above 12-18 Gy in different cancer cells, and attenuates their immunogenicity by degrading DNA that accumulates in the cytosol upon radiation. Cytosolic DNA stimulates secretion of interferon-β by cancer cells following activation of the DNA sensor cGAS and its downstream effector STING...
June 9, 2017: Nature Communications
https://www.readbyqxmd.com/read/28597662/chitosan-hyaluronic-acid-nanoparticles-rational-design-revisited-for-rna-delivery
#8
Enrique Lallana, Julio M Rios de la Rosa, Annalisa Tirella, Maria Pelliccia, Arianna Gennari, Ian J Stratford, Sanyogitta Puri, Marianne Ashford, Nicola Tirelli
Chitosan/hyaluronic acid (HA) nanoparticles can be used to deliver an RNA/DNA cargo to cells overexpressing HA receptors such as CD44. For these systems, unequivocal links have not been established yet between chitosan macromolecular (molecular weight; degree of deacetylation, i.e., charge density) and nanoparticle variables (complexation strength, i.e., stability; nucleic acid protection; internalization rate) on one hand, and transfection efficiency on the other hand. Here, we have focused on the role of avidity on transfection efficiency in the CD44-expressing HCT-116 as a cellular model; we have employed two differently sized payloads (a large luciferase-encoding mRNA and a much smaller anti-Luc siRNA), and a small library of chitosans (variable molecular weight and degree of deactylation)...
June 19, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28596706/regulating-sting-in-health-and-disease
#9
REVIEW
Yang Li, Heather L Wilson, Endre Kiss-Toth
The presence of cytosolic double-stranded DNA molecules can trigger multiple innate immune signalling pathways which converge on the activation of an ER-resident innate immune adaptor named "STimulator of INterferon Genes (STING)". STING has been found to mediate type I interferon response downstream of cyclic dinucleotides and a number of DNA and RNA inducing signalling pathway. In addition to its physiological function, a rapidly increasing body of literature highlights the role for STING in human disease where variants of the STING proteins, as well as dysregulated STING signalling, have been implicated in a number of inflammatory diseases...
2017: Journal of Inflammation
https://www.readbyqxmd.com/read/28590414/mtdna-as-a-mediator-for-expression-of-hypoxia-inducible-factor-1%C3%AE-and-ros-in-hypoxic-neuroblastoma-cells
#10
Chung-Wen Kuo, Meng-Han Tsai, Tsu-Kung Lin, Mao-Meng Tiao, Pei-Wen Wang, Jiin-Haur Chuang, Shang-Der Chen, Chia-Wei Liou
Mitochondria consume O₂ to produce ATP and are critical for adaption of hypoxia, but the role of mitochondria in HIF-1α pathway is as yet unclear. In this study, mitochondrial DNA (mtDNA) enriched (SK-N-AS) and depleted (ρ⁰) cells of neuroblastoma were cultured in a hypoxic chamber to simulate a hypoxic condition and then the major components involved in mitochondrial related pathways, hypoxia-inducible factor 1α (HIF-1α) and reactive oxygen species (ROS) were measured. The results showed that hypoxia-stimulated exposure elevated expression of HIF-1α, which was additionally influenced by level of generated ROS within the cytosol...
June 7, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28586364/intracellular-zinc-flux-causes-reactive-oxygen-species-mediated-mitochondrial-dysfunction-leading-to-cell-death-in-leishmania-donovani
#11
Anjali Kumari, Krishn Pratap Singh, Abhishek Mandal, Ranjeet Kumar Paswan, Preeti Sinha, Pradeep Das, Vahab Ali, Sanjiva Bimal, Chandra Shekhar Lal
Leishmaniasis caused by Leishmania parasite is a global threat to public health and one of the most neglected tropical diseases. Therefore, the discovery of novel drug targets and effective drug is a major challenge and an important goal. Leishmania is an obligate intracellular parasite that alternates between sand fly and human host. To survive and establish infections, Leishmania parasites scavenge and internalize nutrients from the host. Nevertheless, host cells presents mechanism like nutrient restriction to inhibit microbial growth and control infection...
2017: PloS One
https://www.readbyqxmd.com/read/28584055/prolonged-fasting-suppresses-mitochondrial-nlrp3-inflammasome-assembly-and-activation-via-sirt3-mediated-activation-of-superoxide-dismutase-2
#12
Javier Traba, Sarah S Geiger, Miriam Kwarteng Siaw, Kim Han, One Hyuk Ra, Richard M Siegel, David Gius, Michael N Sack
Twenty-four hours of fasting is known to blunt activation of the human NLRP3 inflammasome. This effect might be mediated by SIRT3 activation, controlling mitochondrial reactive oxygen species (ROS). To characterize the molecular underpinnings of this fasting effect, we comparatively analyzed the NLRP3 inflammasome response to nutrient deprivation in wildtype and SIRT3-knockout mice. Consistent with previous findings for human NLRP3, prolonged fasting blunted the inflammasome in wildtype mice but not in SIRT3-knockout mice...
June 5, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28580319/the-association-of-oasl-and-type-i-interferons-in-the-pathogenesis-and-survival-of-intracellular-replicating-bacterial-species
#13
REVIEW
Gina Leisching, Ian Wiid, Bienyameen Baker
The type I IFN response quickly became associated with its role in the innate immune response to viral infection. The past few years have seen the significance of IFNs expand in breadth to include non-viral pathogens. Previous work has identified that following viral infection, type I IFN signaling induces the production of the 2'-5'-oligoadenylate synthetase (OAS) family, which include OAS1, OAS2, OAS3, and OAS-like (OASL) protein. OASL was identified to be strongly induced following viral infection through engaging the RNA sensor RIG-I and increasing signaling through this pathway to enhance the anti-viral type I IFN response...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28578026/%C3%AE-pyrrolidinononanophenone-provokes-apoptosis-of-neuronal-cells-through-alterations-in-antioxidant-properties
#14
Toshiyuki Matsunaga, Yoshifumi Morikawa, Kyohei Kamata, Akinobu Shibata, Hidetoshi Miyazono, Yasuhide Sasajima, Koichi Suenami, Kiyohito Sato, Yuji Takekoshi, Satoshi Endo, Ossama El-Kabbani, Akira Ikari
In this study, we found that exposure to α-pyrrolidinononanophenone (α-PNP), a highly lipophilic synthetic cathinone, provokes apoptosis of human neuronal SK-N-SH cells. The drug sensitivity of the cells (50% lethal concentration of 12μM) was similar to those of aortic endothelial and smooth muscle cells, and was higher than those of cells derived from colon, liver, lung and kidney, suggesting that α-PNP overdose and abuse cause serious damage in central nervous and vascular systems. SK-N-SH cell treatment with lethal concentrations (20 and 50μM) of α-PNP facilitated the reactive oxygen species (ROS) production...
May 31, 2017: Toxicology
https://www.readbyqxmd.com/read/28566766/identification-of-a-small-molecule-that-primes-the-type-i-interferon-response-to-cytosolic-dna
#15
Samira Khiar, Marianne Lucas-Hourani, Sébastien Nisole, Nikaïa Smith, Olivier Helynck, Maryline Bourgine, Claude Ruffié, Jean-Philippe Herbeuval, Hélène Munier-Lehmann, Frédéric Tangy, Pierre-Olivier Vidalain
The type I interferon response plays a pivotal role in host defense against infectious agents and tumors, and promising therapeutic approaches rely on small molecules designed to boost this system. To identify such compounds, we developed a high-throughput screening assay based on HEK-293 cells expressing luciferase under the control of Interferon-Stimulated Response Elements (ISRE). An original library of 10,000 synthetic compounds was screened, and we identified a series of 1H-benzimidazole-4-carboxamide compounds inducing the ISRE promoter sequence, specific cellular Interferon-Stimulated Genes (ISGs), and the phosphorylation of Interferon Regulatory Factor (IRF) 3...
May 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28562385/mitochondrial-dna-in-sepsis
#16
John S Harrington, Augustine M K Choi, Kiichi Nakahira
PURPOSE OF REVIEW: Our understanding of critical illness is transforming as we develop a better understanding of the impact pathogen-associated molecular patterns and damage-associated molecular patterns (DAMPs) have on the pathogenesis of disease. Of the known DAMPs, there is a growing interest in mitochondrial DNA (mtDNA) as a DAMP capable of propagating the inflammatory response seen in sepsis and other conditions. In this review, we describe the varying mechanisms by which mtDNA is translocated from mitochondria into cytosol and the extracellular space where it can illicit an inflammatory response...
May 27, 2017: Current Opinion in Critical Care
https://www.readbyqxmd.com/read/28536019/in-vitro-studies-of-dna-condensation-by-bridging-protein-in-a-crowding-environment
#17
Sravani K Ramisetty, Petter Langlete, Rahmi Lale, Rita S Dias
The macromolecules of the bacterial cell occupy 20-40% of the total cytosol volume, and crowded environments have long been known to compact and stabilize DNA. Nevertheless, investigations on DNA-protein binding are generally performed in the absence of crowding, which may yield an incomplete understanding of how nucleoid-assembling proteins work. A family of such proteins, abundant in Gram-negative bacteria, is the histone-like nucleoid structuring proteins (H-NS). Herein, the synergistic role of macromolecular crowding (mimicked using polyethylene glycol, PEG) and H-NS was investigated using fluorescence correlation spectroscopy (FCS) and enzyme protection assays...
May 20, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28533362/cgas-is-essential-for-cellular-senescence
#18
Hui Yang, Hanze Wang, Junyao Ren, Qi Chen, Zhijian J Chen
Cellular senescence is a natural barrier to tumorigenesis and it contributes to the antitumor effects of several therapies, including radiation and chemotherapeutic drugs. Senescence also plays an important role in aging, fibrosis, and tissue repair. The DNA damage response is a key event leading to senescence, which is characterized by the senescence-associated secretory phenotype (SASP) that includes expression of inflammatory cytokines. Here we show that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates innate immunity, is essential for senescence...
June 6, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28531251/ca2-dependent-phosphoregulation-of-the-plasma-membrane-ca2-atpase-aca8-modulates-stimulus-induced-calcium-signatures
#19
Alex Costa, Laura Luoni, Claudia Adriana Marrano, Kenji Hashimoto, Philipp Köster, Sonia Giacometti, Maria Ida De Michelis, Jörg Kudla, Maria Cristina Bonza
Ca2+ signals are transient, hence, upon a stimulus-induced increase in cytosolic Ca2+ concentration, cells have to re-establish resting Ca2+ levels. Ca2+ extrusion is operated by a wealth of transporters, such as Ca2+ pumps and Ca2+/H+ antiporters, which often require a rise in Ca2+ concentration to be activated. Here, we report a regulatory fine-tuning mechanism of the Arabidopsis thaliana plasma membrane-localized Ca2+-ATPase isoform ACA8 that is mediated by calcineurin B-like protein (CBL) and CBL-interacting protein kinase (CIPK) complexes...
May 20, 2017: Journal of Experimental Botany
https://www.readbyqxmd.com/read/28529930/the-central-role-of-ifi204-in-ifn-%C3%AE-release-and-autophagy-activation-during-mycobacterium-bovis-infection
#20
Liu Chunfa, Sun Xin, Li Qiang, Srinand Sreevatsan, Lifeng Yang, Deming Zhao, Xiangmei Zhou
Mycobacterium bovis (M. bovis) is the pathogen of animals and humans that can replicate in the phagosomes of myeloid cells. Cytosolic detection of bacterial products plays a crucial role in initiating the innate immune response, including autophagy activation and interferon-β (IFN-β) release. Although IFN-β release and autophagy activation have been reported during mycobacterium infection, the mechanisms underlying remains poorly defined. Here, we demonstrated that IFN-β release increases in macrophages exposed to M...
2017: Frontiers in Cellular and Infection Microbiology
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