scholarly journals Cleavage of DNA and RNA by PLD3 and PLD4 limits autoinflammatory triggering by multiple sensors

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Amanda L. Gavin ◽  
Deli Huang ◽  
Tanya R. Blane ◽  
Therese C. Thinnes ◽  
Yusuke Murakami ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Inflammatory Diseases ◽  
Type I ◽  
Multiple Sensors ◽  
Dna And Rna ◽  
Elevated Type ◽  
Minor Contribution ◽  
Ifn Γ ◽  
A Minor ◽  
Rna And Dna

AbstractPhospholipase D3 (PLD3) and PLD4 polymorphisms have been associated with several important inflammatory diseases. Here, we show that PLD3 and PLD4 digest ssRNA in addition to ssDNA as reported previously. Moreover, Pld3−/−Pld4−/− mice accumulate small ssRNAs and develop spontaneous fatal hemophagocytic lymphohistiocytosis (HLH) characterized by inflammatory liver damage and overproduction of Interferon (IFN)-γ. Pathology is rescued in Unc93b13d/3dPld3−/−Pld4−/− mice, which lack all endosomal TLR signaling; genetic codeficiency or antibody blockade of TLR9 or TLR7 ameliorates disease less effectively, suggesting that both RNA and DNA sensing by TLRs contributes to inflammation. IFN-γ made a minor contribution to pathology. Elevated type I IFN and some other remaining perturbations in Unc93b13d/3dPld3−/−Pld4−/− mice requires STING (Tmem173). Our results show that PLD3 and PLD4 regulate both endosomal TLR and cytoplasmic/STING nucleic acid sensing pathways and have implications for the treatment of nucleic acid-driven inflammatory disease.

scholarly journals The Nucleic Acid Binding Activity of Bleomycin Hydrolase Is Involved in Bleomycin Detoxification

1998 ◽  
Vol 18 (6) ◽  
pp. 3580-3585 ◽  
Author(s):  
Wenjin Zheng ◽  
Stephen Albert Johnston
Keyword(s):  
Nucleic Acid ◽  
Binding Activity ◽  
Dual Function ◽  
Nucleic Acid Binding ◽  
Peptide Cleavage ◽  
Dna And Rna ◽  
Double Stranded Dna ◽  
Bleomycin Hydrolase ◽  
Nucleic Acid Binding Activity ◽  
Rna And Dna

ABSTRACT Yeast bleomycin hydrolase, Gal6p, is a cysteine peptidase that detoxifies the anticancer drug bleomycin. Gal6p is a dual-function protein capable of both nucleic acid binding and peptide cleavage. We now demonstrate that Gal6p exhibits sequence-independent, high-affinity binding to single-stranded DNA, nicked double-stranded DNA, and RNA. A region of the protein that is involved in binding both RNA and DNA substrates is delineated. Immunolocalization reveals that the Gal6 protein is chiefly cytoplasmic and thus may be involved in binding cellular RNAs. Variant Gal6 proteins that fail to bind nucleic acid also exhibit reduced ability to protect cells from bleomycin toxicity, suggesting that the nucleic acid binding activity of Gal6p is important in bleomycin detoxification and may be involved in its normal biological functions.

scholarly journals Type I interferons in host defence and inflammatory diseases

2019 ◽  
Vol 6 (1) ◽  
pp. e000336 ◽  
Author(s):  
Mary K. Crow ◽  
Lars Ronnblom
Keyword(s):  
Nucleic Acid ◽  
Inflammatory Diseases ◽  
Type I Interferons ◽  
Type I ◽  
Type I Ifn ◽  
Type I Ifns ◽  
Pathway Activation ◽  
Functional Consequences ◽  
International Summit ◽  
The Individual

Type I interferons (IFN) can have dual and opposing roles in immunity, with effects that are beneficial or detrimental to the individual depending on whether IFN pathway activation is transient or sustained. Determinants of IFN production and its functional consequences include the nature of the microbial or nucleic acid stimulus, the type of nucleic acid sensor involved in inducing IFN, the predominant subtype of type I IFN produced and the immune ecology of the tissue at the time of IFN expression. When dysregulated, the type I IFN system drives many autoimmune and non-autoimmune inflammatory diseases, including SLE and the tissue inflammation associated with chronic infection. The type I IFN system may also contribute to outcomes for patients affected by solid cancers or myocardial infarction. Significantly more research is needed to discern the mechanisms of induction and response to type I IFNs across these diseases, and patient endophenotyping may help determine whether the cytokine is acting as ‘friend’ or ‘foe’, within a particular patient, and at the time of treatment. This review summarises key concepts and discussions from the second International Summit on Interferons in Inflammatory Diseases, during which expert clinicians and scientists evaluated the evidence for the role of type I IFNs in autoimmune and other inflammatory diseases.

scholarly journals Changes in nucleic acid and protein levels during in vitro germ¬nation and elongation of Lilium longifforum cv. "Ace" polleni

2014 ◽  
Vol 50 (1-2) ◽  
pp. 39-50
Author(s):  
William V. Dashek
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Total Protein ◽  
Time Course ◽  
Lilium Longiflorum ◽  
Protein Levels ◽  
Dna And Rna ◽  
Rna And Dna ◽  
Rna Levels

While changes in nucleic acid and protein levels during germination and subsequent tube elongation have been determined for a number of pollens, they have not been extensively examined for <em>in vitro</em> grown <em>Lilium longiflorum</em>, cv. `Ace' pollen. Nucleic acids and proteins were extracted with cold trichloroacetic acrid (TCA), cold-hot TCA or cold TCA and potassium hydroxide-perchloric acid (KOH-HClO<sub>4</sub>). Following extraction, RNA, DNA and total protein were assayed colorimetrically with orcinol, diphenylamine and Folin-Phenol reagents, respectively. Extraction of 500 x g supernatants with KOH-HClO<sub>4</sub>, yielded less RNA than either of the TCA-extraction procedures which gave similar nucleic acids and protein recoveries. Whereas total protein levels decreased initially and then increased during 36 h, RNA and DNA levels rose throughout the time-course. Precipitation and quaritiation of nucleic acids and protein from homogenized and soaicated 500 x g pellets resulted in time-dependent alterations in levels of macromolecules which differed from those for 500 x g supernatants. Whereas DNA and RNA levels increased and then decreased over 36 h, total protein levels remained constant for 12 h and then declined during the : next 24 h. Addition of the data obtained for 500 x g supernatants to those for 500 x g pellets revealed that total protein levels increased 2.4 times for the first 12 h and thereafter remained constant, that RNA levels increased 9.8 times for the first 12 h and then levelled off and that the DNA content rose more than 5 times over 36 h.

scholarly journals The Cytomegalovirus Tegument Protein UL35 Antagonizes Pattern Recognition Receptor-Mediated Type I IFN Transcription

2020 ◽  
Vol 8 (6) ◽  
pp. 790 ◽  
Author(s):  
Markus Fabits ◽  
Vladimir Gonçalves Magalhães ◽  
Baca Chan ◽  
Virginie Girault ◽  
Endrit Elbasani ◽  
...  
Keyword(s):  
Pattern Recognition ◽  
Ectopic Expression ◽  
Pattern Recognition Receptor ◽  
Luciferase Reporter ◽  
Tegument Protein ◽  
Type I ◽  
Type I Ifn ◽  
Dna And Rna ◽  
Elevated Type ◽  
Recognition Receptor

The rapid activation of pattern recognition receptor (PRR)-mediated type I interferon (IFN) signaling is crucial for the host response to infection. In turn, human cytomegalovirus (HCMV) must evade this potent response to establish life-long infection. Here, we reveal that the HCMV tegument protein UL35 antagonizes the activation of type I IFN transcription downstream of the DNA and RNA sensors cGAS and RIG-I, respectively. We show that ectopic expression of UL35 diminishes the type I IFN response, while infection with a recombinant HCMV lacking UL35 induces an elevated type I IFN response compared to wildtype HCMV. With a series of luciferase reporter assays and the analysis of signaling kinetics upon HCMV infection, we observed that UL35 downmodulates PRR signaling at the level of the key signaling factor TANK-binding kinase 1 (TBK1). Finally, we demonstrate that UL35 and TBK1 co-immunoprecipitate when co-expressed in HEK293T cells. In addition, we show that a previously reported cellular binding partner of UL35, O-GlcNAc transferase (OGT), post-translationally GlcNAcylates UL35, but that this modification is not required for the antagonizing effect of UL35 on PRR signaling. In summary, we have identified UL35 as the first HCMV protein to antagonize the type I IFN response at the level of TBK1, thereby enriching our understanding of how this important herpesvirus escapes host immune responses.

scholarly journals Signaling Through Nucleic Acid Sensors and Their Roles in Inflammatory Diseases

2021 ◽  
Vol 11 ◽  
Author(s):  
Haruna Okude ◽  
Daisuke Ori ◽  
Taro Kawai
Keyword(s):  
Nucleic Acid ◽  
Immune Responses ◽  
Nucleic Acids ◽  
Inflammatory Diseases ◽  
Host Cells ◽  
Type I Interferons ◽  
Type I ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Sensor Molecules

Recognition of pathogen-derived nucleic acids by pattern-recognition receptors (PRRs) is essential for eliciting antiviral immune responses by inducing the production of type I interferons (IFNs) and proinflammatory cytokines. Such responses are a prerequisite for mounting innate and pathogen-specific adaptive immune responses. However, host cells also use nucleic acids as carriers of genetic information, and the aberrant recognition of self-nucleic acids by PRRs is associated with the onset of autoimmune or autoinflammatory diseases. In this review, we describe the mechanisms of nucleic acid sensing by PRRs, including Toll-like receptors, RIG-I-like receptors, and DNA sensor molecules, and their signaling pathways as well as the disorders caused by uncontrolled or unnecessary activation of these PRRs.

scholarly journals Induction of IFN-αβ enables Listeria monocytogenes to suppress macrophage activation by IFN-γ

2010 ◽  
Vol 207 (2) ◽  
pp. 327-337 ◽  
Author(s):  
Manira Rayamajhi ◽  
Jessica Humann ◽  
Kristi Penheiter ◽  
Karl Andreasen ◽  
Laurel L. Lenz
Keyword(s):  
Listeria Monocytogenes ◽  
Cross Talk ◽  
Inflammatory Diseases ◽  
Systemic Infection ◽  
Host Susceptibility ◽  
Type I ◽  
Activation Markers ◽  
Beneficial Effects ◽  
Immunological Effects ◽  
Ifn Γ

Production of type I interferon (IFN; IFN-αβ) increases host susceptibility to Listeria monocytogenes, whereas type II IFN (IFN-γ) activates macrophages to resist infection. We show that these opposing immunological effects of IFN-αβ and IFN-γ occur because of cross talk between the respective signaling pathways. We found that cultured macrophages infected with L. monocytogenes were refractory to IFN-γ treatment as a result of down-regulation of the IFN-γ receptor (IFNGR). The soluble factor responsible for these effects was identified as host IFN-αβ. Accordingly, macrophages and dendritic cells (DCs) showed reduced IFNGR1 expression and reduced responsiveness to IFN-γ during systemic infection of IFN-αβ–responsive mice. Furthermore, the increased resistance of mice lacking the IFN-αβ receptor (IFNAR−/−) to L. monocytogenes correlated with increased expression of IFN-γ–dependent activation markers by macrophages and DCs and was reversed by depletion of IFN-γ. Thus, IFN-αβ produced in response to bacterial infection and other stimuli antagonizes the host response to IFN-γ by down-regulating the IFNGR. Such cross talk permits prioritization of IFN-αβ–type immune responses and may contribute to the beneficial effects of IFN-β in treatment of inflammatory diseases such as multiple sclerosis.

scholarly journals Self-Awareness: Nucleic Acid–Driven Inflammation and the Type I Interferonopathies

2019 ◽  
Vol 37 (1) ◽  
pp. 247-267 ◽  
Author(s):  
Carolina Uggenti ◽  
Alice Lepelley ◽  
Yanick J. Crow
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Evolutionary Strategy ◽  
Type I ◽  
Self Awareness ◽  
Inborn Errors ◽  
Biological Challenge ◽  
Disease States ◽  
Dna And Rna ◽  
Type I Interferonopathies

Recognition of foreign nucleic acids is the primary mechanism by which a type I interferon–mediated antiviral response is triggered. Given that human cells are replete with DNA and RNA, this evolutionary strategy poses an inherent biological challenge, i.e., the fundamental requirement to reliably differentiate self–nucleic acids from nonself nucleic acids. We suggest that the group of Mendelian inborn errors of immunity referred to as the type I interferonopathies relate to a breakdown of self/nonself discrimination, with the associated mutant genotypes involving molecules playing direct or indirect roles in nucleic acid signaling. This perspective begs the question as to the sources of self-derived nucleic acids that drive an inappropriate immune response. Resolving this question will provide fundamental insights into immune tolerance, antiviral signaling, and complex autoinflammatory disease states. Here we develop these ideas, discussing type I interferonopathies within the broader framework of nucleic acid–driven inflammation.

scholarly journals ASAXS quantifies counterion distributions around DNA and RNA

2014 ◽  
Vol 70 (a1) ◽  
pp. C1579-C1579
Author(s):  
Lois Pollack
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acid Structure ◽  
Ion Distribution ◽  
Dna And Rna ◽  
Charge Interaction ◽  
The Relationship ◽  
Oppositely Charged ◽  
Scattering Signal ◽  
Acid Structure ◽  
Rna And Dna

Because both RNA and DNA carry large negative charge, interaction with oppositely charged partners is required for folding to functional structures. For example, counterions fold RNA and condense DNA. Despite these important roles, ion detection remains elusive. I describe the application of anomalous SAXS methods that highlight the contribution to the scattering signal arising from counterions [1]. In addition to measuring ion distribution, we also count the number of excess ions surrounding a nucleic acid structure [2,3]. Taken together, measurements of ion number and spatial distribution provide an understanding of the relationship between counterions and nucleic acid structure. Present ASAXS work in the Pollack lab is supported by the NIH through grants R01 GM085062 and R01 GM099450.

High-resolution nucleic acid sequence mapping via in situ hybridization at the Electron Microscope level

1995 ◽  
Vol 53 ◽  
pp. 752-753
Author(s):  
B.A. Hamkalo ◽  
S. Narayanswami ◽  
A.P. Kausch
Keyword(s):  
Nucleic Acid ◽  
Interphase Nucleus ◽  
Genome Mapping ◽  
Precise Location ◽  
Electron Microscope Level ◽  
Rna Sequences ◽  
Fundamental Interest ◽  
Whole Cells ◽  
Dna And Rna

The availability of nonradioactive methods to label nucleic acids an the resultant rapid and greater sensitivity of detection has catapulted the technique of in situ hybridization to become the method of choice to locate of specific DNA and RNA sequences on chromosomes and in whole cells in cytological preparations in many areas of biology. It is being applied to problems of fundamental interest to basic cell and molecular biologists such as the organization of the interphase nucleus in the context of putative functional domains; it is making major contributions to genome mapping efforts; and it is being applied to the analysis of clinical specimens. Although fluorescence detection of nucleic acid hybrids is routinely used, certain questions require greater resolution. For example, very closely linked sequences may not be separable using fluorescence; the precise location of sequences with respect to chromosome structures may be below the resolution of light microscopy(LM); and the relative positions of sequences on very small chromosomes may not be feasible.

Electron microscopy analysis of degenerating pancreatic ß cells in transgenic mice expressing the MHC Class I antigen Dd

1990 ◽  
Vol 48 (3) ◽  
pp. 548-549
Author(s):  
T. A. Stewart ◽  
D. Liggitt ◽  
S. Pitts ◽  
L. Martin ◽  
M. Siegel ◽  
...  
Keyword(s):  
Type I Diabetes ◽  
Disease Process ◽  
Class Ii ◽  
Class I ◽  
Type I ◽  
Aberrant Expression ◽  
Mhc Molecules ◽  
Endogenous Insulin ◽  
Class Ii Mhc ◽  
Ifn Γ

Insulin-dependant (Type I) diabetes mellitus (IDDM) is a metabolic disorder resulting from the lack of endogenous insulin secretion. The disease is thought to result from the autoimmune mediated destruction of the insulin producing ß cells within the islets of Langerhans. The disease process is probably triggered by environmental agents, e.g. virus or chemical toxins on a background of genetic susceptibility associated with particular alleles within the major histocompatiblity complex (MHC). The relation between IDDM and the MHC locus has been reinforced by the demonstration of both class I and class II MHC proteins on the surface of ß cells from newly diagnosed patients as well as mounting evidence that IDDM has an autoimmune pathogenesis. In 1984, a series of observations were used to advance a hypothesis, in which it was suggested that aberrant expression of class II MHC molecules, perhaps induced by gamma-interferon (IFN γ) could present self antigens and initiate an autoimmune disease. We have tested some aspects of this model and demonstrated that expression of IFN γ by pancreatic ß cells can initiate an inflammatory destruction of both the islets and pancreas and does lead to IDDM.

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