Ribonuclease H2 in health and disease

2014 ◽  
Vol 42 (4) ◽  
pp. 717-725 ◽  
Author(s):  
Martin A.M. Reijns ◽  
Andrew P. Jackson
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Viral Infection ◽  
Genome Stability ◽  
Innate Immune ◽  
Nucleic Acid Metabolism ◽  
Developmental Studies ◽  
Cellular Processes ◽  
Immune Sensing ◽  
Rnase H2

Innate immune sensing of nucleic acids provides resistance against viral infection and is important in the aetiology of autoimmune diseases. AGS (Aicardi–Goutières syndrome) is a monogenic autoinflammatory disorder mimicking in utero viral infection of the brain. Phenotypically and immunologically, it also exhibits similarities to SLE (systemic lupus erythaematosus). Three of the six genes identified to date encode components of the ribonuclease H2 complex. As all six encode enzymes involved in nucleic acid metabolism, it is thought that pathogenesis involves the accumulation of nucleic acids to stimulate an inappropriate innate immune response. Given that AGS is a monogenic disorder with a defined molecular basis, we use it as a model for common autoimmune disease to investigate cellular processes and molecular pathways responsible for nucleic-acid-mediated autoimmunity. These investigations have also provided fundamental insights into the biological roles of the RNase H2 endonuclease enzyme. In the present article, we describe how human RNase H2 and its role in AGS were first identified, and give an overview of subsequent structural, biochemical, cellular and developmental studies of this enzyme. These investigations have culminated in establishing this enzyme as a key genome-surveillance enzyme required for mammalian genome stability.

Detection of Microbial Infections Through Innate Immune Sensing of Nucleic Acids

2018 ◽  
Vol 72 (1) ◽  
pp. 447-478 ◽  
Author(s):  
Xiaojun Tan ◽  
Lijun Sun ◽  
Jueqi Chen ◽  
Zhijian J. Chen
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Immune Defense ◽  
Innate Immune ◽  
Type I Interferons ◽  
Microbial Pathogens ◽  
Type I ◽  
Immune Recognition ◽  
Microbial Infection ◽  
Microbial Infections

Microbial infections are recognized by the innate immune system through germline-encoded pattern recognition receptors (PRRs). As most microbial pathogens contain DNA and/or RNA during their life cycle, nucleic acid sensing has evolved as an essential strategy for host innate immune defense. Pathogen-derived nucleic acids with distinct features are recognized by specific host PRRs localized in endolysosomes and the cytosol. Activation of these PRRs triggers signaling cascades that culminate in the production of type I interferons and proinflammatory cytokines, leading to induction of an antimicrobial state, activation of adaptive immunity, and eventual clearance of the infection. Here, we review recent progress in innate immune recognition of nucleic acids upon microbial infection, including pathways involving endosomal Toll-like receptors, cytosolic RNA sensors, and cytosolic DNA sensors. We also discuss the mechanisms by which infectious microbes counteract host nucleic acid sensing to evade immune surveillance.

scholarly journals TBK1, a central kinase in innate immune sensing of nucleic acids and beyond

2020 ◽  
Vol 52 (7) ◽  
pp. 757-767 ◽  
Author(s):  
Ruyuan Zhou ◽  
Qian Zhang ◽  
Pinglong Xu
Keyword(s):  
Nucleic Acids ◽  
Cell Biology ◽  
Innate Immune ◽  
Type I ◽  
Interferon Stimulated Genes ◽  
Immune Sensing ◽  
Mitochondrial Antiviral Signaling ◽  
I Kappa B Kinase ◽  
Innate Immune Sensing ◽  
Mitochondrial Antiviral Signaling Protein

Abstract Sensing of intracellular and extracellular environments is one of the fundamental processes of cell. Surveillance of aberrant nucleic acids, derived either from invading pathogens or damaged organelle, is conducted by pattern recognition receptors (PRRs) including RIG-I-like receptors, cyclic GMP-AMP synthase, absent in melanoma 2, and a few members of toll-like receptors. TANK-binding kinase 1 (TBK1), along with its close analogue I-kappa-B kinase epsilon, is a central kinase in innate adaptor complexes linking activation of PRRs to mobilization of transcriptional factors that transcribe proinflammatory cytokines, type I interferon (IFN-α/β), and myriads interferon stimulated genes. However, it still remains elusive for the precise mechanisms of activation and execution of TBK1 in signaling platforms formed by innate adaptors mitochondrial antiviral signaling protein (MAVS), stimulator of interferon genes protein (STING), and TIR-domain-containing adapter-inducing interferon-β (TRIF), as well as its complex regulations. An atlas of TBK1 substrates is in constant expanding, setting TBK1 as a key node of signaling network and a dominant player in contexts of cell biology, animal models, and human diseases. Here, we review recent advancements of activation, regulations, and functions of TBK1 under these physiological and pathological contexts.

scholarly journals PSMB1 Negatively Regulates the Innate Antiviral Immunity by Facilitating Degradation of IKK-ε

Viruses ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 99
Author(s):  
Fangyi Wu ◽  
Zhenmin Niu ◽  
Bin Zhou ◽  
Pengcheng Li ◽  
Feng Qian
Keyword(s):  
Viral Infection ◽  
Rna Virus ◽  
Cell Cycle Control ◽  
Ubiquitin Proteasome System ◽  
Innate Immune ◽  
Negative Regulator ◽  
Viral Immunity ◽  
Chemokine Production ◽  
Cellular Processes ◽  
Innate Immune Signaling

Proteasome is a large protein complex, which degrades most intracellular proteins. It regulates numerous cellular processes, including the removal of misfolded or unfolded proteins, cell cycle control, and regulation of apoptosis. However, the function of proteasome subunits in viral immunity has not been well characterized. In this study, we identified PSMB1, a member of the proteasome β subunits (PSMB) family, as a negative regulator of innate immune responses during viral infection. Knockdown of PSMB1 enhanced the RNA virus-induced cytokine and chemokine production. Overexpression of PSMB1 abolished virus-induced activation of the interferon-stimulated response element (ISRE) and interferon beta (IFNβ) promoters. Mechanistically, PSMB1 inhibited the activation of RIG-I-like receptor (RLR) and Toll-like receptor 3 (TLR3) signaling pathways. PSMB1 was induced after viral infection and its interaction with IKK-ε promoted degradation of IKK-ε through the ubiquitin-proteasome system. Collectively, our study demonstrates PSMB1 is an important regulator of innate immune signaling.

scholarly journals Helicase Mechanisms During Homologous Recombination inSaccharomyces cerevisiae

2019 ◽  
Vol 48 (1) ◽  
pp. 255-273 ◽  
Author(s):  
J. Brooks Crickard ◽  
Eric C. Greene
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Nucleic Acid ◽  
Homologous Recombination ◽  
Nucleic Acids ◽  
Acid Metabolism ◽  
Model Organism ◽  
Nucleic Acid Metabolism ◽  
Repair Pathway ◽  
Unidirectional Movement ◽  
Nucleoprotein Complexes

Helicases are enzymes that move, manage, and manipulate nucleic acids. They can be subdivided into six super families and are required for all aspects of nucleic acid metabolism. In general, all helicases function by converting the chemical energy stored in the bond between the gamma and beta phosphates of adenosine triphosphate into mechanical work, which results in the unidirectional movement of the helicase protein along one strand of a nucleic acid. The results of this translocation activity can range from separation of strands within duplex nucleic acids to the physical remodeling or removal of nucleoprotein complexes. In this review, we focus on describing key helicases from the model organism Saccharomyces cerevisiae that contribute to the regulation of homologous recombination, which is an essential DNA repair pathway for fixing damaged chromosomes.

scholarly journals Innate immune sensing of nucleic acids from mycobacteria

2014 ◽  
Vol 16 (12) ◽  
pp. 991-997 ◽  
Author(s):  
Lívia Harumi Yamashiro ◽  
Sérgio Costa Oliveira ◽  
André Báfica
Keyword(s):  
Nucleic Acids ◽  
Innate Immune ◽  
Immune Sensing ◽  
Innate Immune Sensing

Superfamily I helicases as modular components of DNA-processing machines

2011 ◽  
Vol 39 (2) ◽  
pp. 413-423 ◽  
Author(s):  
Mark S. Dillingham
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Molecular Mechanisms ◽  
Acid Metabolism ◽  
Nucleic Acid Metabolism ◽  
Cellular Functions ◽  
Dna Helicases ◽  
Wide Range ◽  
Look Back ◽  
Partner Proteins

Helicases are a ubiquitous and abundant group of motor proteins that couple NTP binding and hydrolysis to processive unwinding of nucleic acids. By targeting this activity to a wide range of specific substrates, and by coupling it with other catalytic functionality, helicases fulfil diverse roles in virtually all aspects of nucleic acid metabolism. The present review takes a look back at our efforts to elucidate the molecular mechanisms of UvrD-like DNA helicases. Using these well-studied enzymes as examples, we also discuss how helicases are programmed by interactions with partner proteins to participate in specific cellular functions.

Biological roles of translin and translin-associated factor-X: RNA metabolism comes to the fore

2010 ◽  
Vol 429 (2) ◽  
pp. 225-234 ◽  
Author(s):  
Alessa Jaendling ◽  
Ramsay J. McFarlane
Keyword(s):  
Nucleic Acid ◽  
Cell Biology ◽  
Genome Stability ◽  
Growth Regulation ◽  
Biological Activities ◽  
Biochemical Properties ◽  
Nucleic Acid Metabolism ◽  
Factor X ◽  
Nucleic Acid Binding ◽  
Associated Factor

Translin, and its binding partner protein TRAX (translin-associated factor-X) are a paralogous pair of conserved proteins, which have been implicated in a broad spectrum of biological activities, including cell growth regulation, mRNA processing, spermatogenesis, neuronal development/function, genome stability regulation and carcinogenesis, although their precise role in some of these processes remains unclear. Furthermore, translin (with or without TRAX) has nucleic-acid-binding activity and it is apparent that controlling nucleic acid metabolism and distribution are central to the biological role(s) of this protein and its partner TRAX. More recently, translin and TRAX have together been identified as enhancer components of an RNAi (RNA interference) pathway in at least one organism and this might provide critical insight into the biological roles of this enigmatic partnership. In the present review we discuss the biological and the biochemical properties of these proteins that indicate that they play a central and important role in eukaryotic cell biology.

scholarly journals The function and architecture of DEAH/RHA helicases

2011 ◽  
Vol 2 (4) ◽  
pp. 315-326 ◽  
Author(s):  
Yangzi He ◽  
Gregers R. Andersen ◽  
Klaus H. Nielsen
Keyword(s):  
Translational Regulation ◽  
Acid Metabolism ◽  
Structural Features ◽  
Mrna Splicing ◽  
Innate Immune ◽  
Regulatory Proteins ◽  
Nucleic Acid Metabolism ◽  
Rrna Processing ◽  
Macromolecular Complexes ◽  
Cellular Processes

AbstractHelicases are ubiquitous enzymes that participate in every aspect of nucleic acid metabolism. The DEAH/RHA family of helicases are involved in a variety of cellular processes including transcriptional and translational regulation, pre-mRNA splicing, pre-rRNA processing, mRNA export and decay, in addition to the innate immune response. Recently, the first crystal structures of a DEAH/RHA helicase unveiled the unique structural features of this helicase family. These structures furthermore illuminate the molecular mechanism of these proteins and provide a framework for analysis of their interaction with nucleic acids, regulatory proteins and large macromolecular complexes.

scholarly journals CD14 is a coreceptor of Toll-like receptors 7 and 9

2010 ◽  
Vol 207 (12) ◽  
pp. 2689-2701 ◽  
Author(s):  
Christoph L. Baumann ◽  
Irene M. Aspalter ◽  
Omar Sharif ◽  
Andreas Pichlmair ◽  
Stephan Blüml ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Nucleic Acids ◽  
Innate Immune ◽  
Confocal Imaging ◽  
Acid Uptake ◽  
Innate Immune Responses ◽  
Toll Like Receptors ◽  
Molecular Patterns ◽  
Cluster Of Differentiation

Recognition of pathogens by the innate immune system requires proteins that detect conserved molecular patterns. Nucleic acids are recognized by cytoplasmic sensors as well as by endosomal Toll-like receptors (TLRs). It has become evident that TLRs require additional proteins to be activated by their respective ligands. In this study, we show that CD14 (cluster of differentiation 14) constitutively interacts with the MyD88-dependent TLR7 and TLR9. CD14 was necessary for TLR7- and TLR9-dependent induction of proinflammatory cytokines in vitro and for TLR9-dependent innate immune responses in mice. CD14 associated with TLR9 stimulatory DNA in precipitation experiments and confocal imaging. The absence of CD14 led to reduced nucleic acid uptake in macrophages. Additionally, CD14 played a role in the stimulation of TLRs by viruses. Using various types of vesicular stomatitis virus, we showed that CD14 is dispensable for viral uptake but is required for the triggering of TLR-dependent cytokine responses. These data show that CD14 has a dual role in nucleic acid–mediated TLR activation: it promotes the selective uptake of nucleic acids, and it acts as a coreceptor for endosomal TLR activation.

scholarly journals Nucleic Acid Immunity and DNA Damage Response: New Friends and Old Foes

2021 ◽  
Vol 12 ◽  
Author(s):  
Clara Taffoni ◽  
Alizée Steer ◽  
Johanna Marines ◽  
Hanane Chamma ◽  
Isabelle K. Vila ◽  
...  
Keyword(s):  
Dna Damage ◽  
Nucleic Acid ◽  
Nucleic Acids ◽  
Dna Damage Response ◽  
Immune Activation ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
Fine Tuning ◽  
Innate Immune Activation ◽  
Damage Response

The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that cooperate to ensure the repair of genomic lesions. Besides their repair functions, several DDR proteins have emerged as involved in the onset of inflammatory responses. In particular, several actors of the DDR have been reported to elicit innate immune activation upon detection of cytosolic pathological nucleic acids. Conversely, pattern recognition receptors (PRRs), initially described as dedicated to the detection of cytosolic immune-stimulatory nucleic acids, have been found to regulate DDR. Thus, although initially described as operating in specific subcellular localizations, actors of the DDR and nucleic acid immune sensors may be involved in interconnected pathways, likely influencing the efficiency of one another. Within this mini review, we discuss evidences for the crosstalk between PRRs and actors of the DDR. For this purpose, we mainly focus on cyclic GMP-AMP (cGAMP) synthetase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16), as major PRRs involved in the detection of aberrant nucleic acid species, and components of the DNA-dependent protein kinase (DNA-PK) complex, involved in the repair of double strand breaks that were recently described to qualify as potential PRRs. Finally, we discuss how the crosstalk between DDR and nucleic acid-associated Interferon responses cooperate for the fine-tuning of innate immune activation, and therefore dictate pathological outcomes. Understanding the molecular determinants of such cooperation will be paramount to the design of future therapeutic approaches.

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