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cytosolic DNA

Jin Cai, Gengze Wu, Pedro A Jose, Chunyu Zeng
Extracellular vesicles (EVs) are small membrane vesicles including exosomes and shedding vesicles that mediated a cell-to-cell communication. EVs are released from almost all cell types under both physiological and pathological conditions and incorporate nuclear and cytoplasmic molecules for intercellular delivery. Besides protein, mRNA, and microRNA of these molecules, as recent studies show, specific DNA are prominently packaged into EVs. It appears likely that some of exosomes or shedding vesicles, bearing nuclear molecules are released upon bubble-like blebs...
October 14, 2016: Experimental Cell Research
Stefanie Luecke, Søren R Paludan
Nucleic acids sensors of the innate immune system recognize various RNA and DNA structures during infection to induce transcription of interferon and pro-inflammatory cytokines and activation of inflammasomes. Cytosolic RNA is recognized by RIG-I and MDA5, while intracellular DNA is sensed among others by cGAS, AIM2, IFI16 and RNA polymerase III. The diversity of nucleic acid species produced during infection in the cytosol and nucleus and the limited chemical differences between self and non-self nucleic acids challenge the host's innate pattern recognition system to ensure reliable sensing while avoiding immune activation by self nucleic acids...
October 14, 2016: Cytokine
Eun Young Park, Joo-Il Kim, Dong-Gyu Leem, Ji-Sun Shin, Kyung-Tack Kim, Sang Yoon Choi, Myung-Hee Lee, Jung-Hye Choi, Yong Sup Lee, Kyung-Tae Lee
Previously, we reported that (E)-8-acetoxy-2-[2-(3,4-diacetoxyphenyl)ethenyl]-quinazoline (8-ADEQ), a synthetic analogue of resveratrol had anti-inflammatory and G2/M cell cycle arrest activities, but the underlying molecular mechanism of cytotoxic effects of this compound was not determined. In this study, 8-ADEQ displayed potent cytotoxicity and triggered apoptosis in HL-60 cells as evidenced by DNA fragmentation, DNA ladder formation, and the externalization of Annexin V-targeted phosphatidylserine residues in HL-60 cells...
October 13, 2016: Oncology Reports
Dziyana Hnedzko, Dennis W McGee, Yannis A Karamitas, Eriks Rozners
Sequence-selective recognition of complex RNAs in live cells could find broad applications in biology, biomedical research and biotechnology. However, specific recognition of structured RNA is challenging and generally applicable and effective methods are lacking. Recently, we found that peptide nucleic acids (PNAs) were unusually well suited ligands for recognition of double-stranded RNAs. Herein, we report that 2-aminopyridine (M) modified PNAs and their conjugates with lysine and arginine tripeptides form strong (Ka = 9...
October 14, 2016: RNA
Ye Cao, Kai Guan, Xiang He, Congwen Wei, Zirui Zheng, Yanhong Zhang, Shengli Ma, Hui Zhong, Wei Shi
The Yersinia outer protein J (YopJ) plays a pivotal role in evading the host immune response and establishes a persistent infection in host cells after bacterial infection. YopJ is a cysteine protease and can act as a deubiquitinating enzyme that deubiquitinates several targets in multiple signaling pathways. Stimulator of interferon genes (STING) is a critical adapter for the induction of interferon regulatory factor 3 (IRF3) phosphorylation and subsequent production of the cytokines in response to nucleic acids in the cytoplasm...
October 11, 2016: Biochimica et Biophysica Acta
Rebecca Baum, Shruti Sharma, Jason M Organ, Christopher Jakobs, Veit Hornung, David B Burr, Ann Marshak-Rothstein, Katherine A Fitzgerald, Ellen M Gravallese
OBJECTIVE: Cytosolic DNA sensors detect microbial DNA and promote type I interferon and pro-inflammatory cytokine production through the adaptor stimulator of interferon genes (STING) to resolve infection. Endogenous DNA also engages the STING pathway, contributing to autoimmune disease. We identified a novel role for STING in bone in arthritic DNase II/IFNaR double deficient (DKO) mice, and sought to define the bone phenotype in these mice and to address mechanism. METHODS: Bone parameters were evaluated in DKO, STING/DNaseII/IFNaR triple deficient and control mice by microcomputed tomography and histomorphometry...
October 14, 2016: Arthritis & Rheumatology
A R Jayakumar, X Y Tong, N Shamaladevi, S Barcelona, G Gaidosh, A Agarwal, M D Norenberg
Transactivating DNA-binding protein-43 (TDP-43) inclusions and the accumulation of phosphorylated and ubiquitinated tau proteins (p-tau) have been identified in postmortem brain specimens from patients with chronic traumatic encephalopathy (CTE). To examine whether these proteins contribute to the development of CTE, we utilized an in vitro trauma system known to reproduce many of the findings observed in humans and experimental animals with traumatic brain injury. Accordingly, we examined the role of TDP-43 and Tau in an in vitro model of trauma, and determined whether these proteins contribute to the defective neuronal integrity associated with CNS trauma...
October 13, 2016: Journal of Neurochemistry
Santhosh Kumar Sariki, Pushpendra Kumar Sahu, Upendarrao Golla, Vikash Singh, Gajendra Kumar Azad, Raghuvir S Tomar
Mutations in the Senataxin gene, SETX are known to cause the neurodegenerative disorders, ataxia with oculomotor apraxia type 2 (AOA2) and amyotrophic lateral sclerosis 4 (ALS4). However, the mechanism underlying disease pathogenesis is still unclear. The Senataxin N-terminal protein-interaction and C-terminal RNA/DNA helicase domains are conserved in the Saccharomyces cerevisiae homolog, Sen1p. Using genome-wide expression analysis, we first show alterations in key cellular pathways such as; redox, unfolded protein response and TOR in the yeastsen1ΔN mutant (N terminal truncation)...
October 8, 2016: FEBS Journal
M-L Liu, K J Williams, V P Werth
During apoptosis or activation, cells can release a subcellular structure, called a membrane microvesicle (also known as microparticle) into the extracellular environment. Microvesicles bud-off as a portion of cell membrane with its associated proteins and lipids surrounding a cytosolic core that contains intracellular proteins, lipids, and nucleic acids (DNA, RNA, siRNA, microRNA, lncRNA). Biologically active molecules on the microvesicle surface and encapsulated within can act on recipient cells as a novel mode of intercellular communication...
2016: Advances in Clinical Chemistry
Junwei Xu, Lu Lu, Jing Lu, Jihui Xia, Hongjin Lu, Lin Yang, Wensheng Xia, Shihai Shen
BACKGROUND: Recent evidence suggests that CD200 fusion protein (CD200Fc), a CD200R1 agonist may attenuate inflammatory responses in autoimmune diseases and neuro-degeneration. While, little is known about the function of CD200Fc in cigarette smoke extract (CSE)-induced mouse Cardiac Microvascular Endothelial Cells (mCMECs). The present study was designed to elucidate the effects of CD200Fc on CSE-induced vascular endothelial barrier (VEB) dysfunction and inflammatory responses, which is a highly clinically relevant model of smoking related cardiovascular diseases...
October 3, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Eileen E Parkes, Steven M Walker, Laura E Taggart, Nuala McCabe, Laura A Knight, Richard Wilkinson, Karen D McCloskey, Niamh E Buckley, Kienan I Savage, Manuel Salto-Tellez, Stephen McQuaid, Mary T Harte, Paul B Mullan, D Paul Harkin, Richard D Kennedy
BACKGROUND: Previously we identified a DNA damage response-deficient (DDRD) molecular subtype within breast cancer. A 44-gene assay identifying this subtype was validated as predicting benefit from DNA-damaging chemotherapy. This subtype was defined by interferon signaling. In this study, we address the mechanism of this immune response and its possible clinical significance. METHODS: We used immunohistochemistry (IHC) to characterize immune infiltration in 184 breast cancer samples, of which 65 were within the DDRD subtype...
January 2017: Journal of the National Cancer Institute
Jianli Tao, Xiang Zhou, Zhengfan Jiang
Innate immunity is the first line of host defense against invading pathogens. The detection of aberrant nucleic acids which represent some conserved PAMPs triggers robust type I IFN-mediated innate immune responses. Host- or pathogen-derived cytosolic DNA binds and activates the DNA sensor cGAS, which synthesizes the second messenger 2'3'-cGAMP and triggers STING-dependent downstream signaling. Here, we highlight recent progress in cGAS-cGAMP-STING, the Three Musketeers of cytosolic DNA sensing and signaling, and their essential roles in infection, autoimmune diseases, and cancer...
October 5, 2016: IUBMB Life
Jolien Vermeire, Ferdinand Roesch, Daniel Sauter, Réjane Rua, Dominik Hotter, Anouk Van Nuffel, Hanne Vanderstraeten, Evelien Naessens, Veronica Iannucci, Alessia Landi, Wojciech Witkowski, Ann Baeyens, Frank Kirchhoff, Bruno Verhasselt
Several pattern-recognition receptors sense HIV-1 replication products and induce type I interferon (IFN-I) production under specific experimental conditions. However, it is thought that viral sensing and IFN induction are virtually absent in the main target cells of HIV-1 in vivo. Here, we show that activated CD4(+) T cells sense HIV-1 infection through the cytosolic DNA sensor cGAS and mount a bioactive IFN-I response. Efficient induction of IFN-I by HIV-1 infection requires proviral integration and is regulated by newly expressed viral accessory proteins: Vpr potentiates, while Vpu suppresses cGAS-dependent IFN-I induction...
October 4, 2016: Cell Reports
Catalina Ana Rosselló, Lisa Lindström, Johan Glindre, Greta Eklund, Maria Alvarado-Kristensson
The cytosolic role of γ-tubulin as a microtubule organizer has been studied thoroughly, but its nuclear function is poorly understood. Here, we show that γ-tubulin is located throughout the chromatin of demembranated Xenopus laevis sperm and, as the nucleus is formed, γ-tubulin recruits lamin B3 and nuclear membranes. Immunodepletion of γ-tubulin impairs X. laevis assembly of both the lamina and the nuclear membrane. During nuclear formation in mammalian cell lines, γ-tubulin establishes a cellular protein boundary around chromatin that coordinates nuclear assembly of the daughter nuclei...
September 2016: Heliyon
Si Ming Man, Rajendra Karki, Miwa Sasai, David E Place, Sannula Kesavardhana, Jamshid Temirov, Sharon Frase, Qifan Zhu, R K Subbarao Malireddi, Teneema Kuriakose, Jennifer L Peters, Geoffrey Neale, Scott A Brown, Masahiro Yamamoto, Thirumala-Devi Kanneganti
The inflammasome is an intracellular signaling complex, which on recognition of pathogens and physiological aberration, drives activation of caspase-1, pyroptosis, and the release of the pro-inflammatory cytokines IL-1β and IL-18. Bacterial ligands must secure entry into the cytoplasm to activate inflammasomes; however, the mechanisms by which concealed ligands are liberated in the cytoplasm have remained unclear. Here, we showed that the interferon-inducible protein IRGB10 is essential for activation of the DNA-sensing AIM2 inflammasome by Francisella novicida and contributed to the activation of the LPS-sensing caspase-11 and NLRP3 inflammasome by Gram-negative bacteria...
October 6, 2016: Cell
Meytal Galilee, Elena Britan-Rosich, Sarah L Griner, Serdar Uysal, Viola Baumgärtel, Don C Lamb, Anthony A Kossiakoff, Moshe Kotler, Robert M Stroud, Ailie Marx, Akram Alian
HIV-1 integrase (IN) catalyzes viral DNA integration into the host genome and facilitates multifunctional steps including virus particle maturation. Competency of IN to form multimeric assemblies is functionally critical, presenting an approach for anti-HIV strategies. Multimerization of IN depends on interactions between the distinct subunit domains and among the flanking protomers. Here, we elucidate an overlooked docking cleft of IN core domain that anchors the N-terminal helix-turn-helix (HTH) motif in a highly preserved and functionally critical configuration...
September 28, 2016: Structure
A D Naveen Kumar, Ganesh Babu Bevara, Laxmi Koteswaramma Kaja, Anil Kumar Badana, Rama Rao Malla
BACKGROUND: Hydrogen peroxide is continuously generated in living cells through metabolic pathways and serves as a source of reactive oxygen species. Beyond the threshold level, it damages cells and causes several human disorders, including cancer. METHODS: Effect of isolated 3-O-methyl quercetin and kaempferol on H2O2 induced cytotoxicity, ROS formation, plasma membrane damage, loss of mitochondrial membrane potential, DNA damage was evaluated in normal liver and lung cells...
September 29, 2016: BMC Complementary and Alternative Medicine
Tianli Xia, Hiroyasu Konno, Glen N Barber
The innate immune regulator STING stimulates cytokine production in response to the presence of cytosolic DNA, which can arise following DNA damage. Extrinsic STING signaling is also needed for antigen-presenting cells (APC) to stimulate antitumor T cell immunity. Here we show that STING signaling is recurrently suppressed in melanoma cells, where this event may enable immune escape after DNA damage. Mechanistically STING signaling was suppressed most frequently by epigenetic silencing of either STING or the cyclic GMP-AMP synthase (cGAS), which generates STING-activating cyclic dinucleotides (CDNs) after binding cytosolic DNA species...
September 28, 2016: Cancer Research
Ren-Jie Wei, Su-Shuan Lin, Wen-Ren Wu, Lih-Ren Chen, Chien-Feng Li, Han-De Chen, Chien-Ting Chou, Ya-Chun Chen, Shih-Shin Liang, Shang-Tao Chien, Yow-Ling Shiue
The objective was to investigate the upstream mechanisms of apoptosis which were triggered by a novel anti-microtubule drug, ABT-751, in hepatocellular carcinoma-derived Huh-7 cells. Effects of ABT-751 were evaluated by immunocytochemistry, flow cytometric, alkaline comet, soft agar, immunoblotting, CytoID, green fluorescent protein-microtubule associated protein 1 light chain 3 beta detection, plasmid transfection, nuclear/cytosol fractionation, coimmunoprecipitation, quantitative reverse transcription-polymerase chain reaction, small-hairpin RNA interference and mitochondria/cytosol fractionation assays...
September 24, 2016: Toxicology and Applied Pharmacology
Amy E Vincent, Hannah S Rosa, Charlotte L Alston, John P Grady, Karolina A Rygiel, Mariana C Rocha, Rita Barresi, Robert W Taylor, Doug M Turnbull
Dysferlinopathies are caused by mutations in the DYSF gene and patients may present with proximal or distal myopathy. Dysferlin is responsible for membrane resealing, and mutations may result in a defect in membrane repair following mechanical or chemical stress, causing an influx of Ca(2+). Since mitochondria are involved in Ca(2+) buffering, we hypothesised that mitochondrial defects may be present in skeletal muscle biopsies from patients with mutations in this gene. The aim was to characterise mitochondrial defects in muscle from patients with dysferlinopathies...
August 29, 2016: Neuromuscular Disorders: NMD
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