The emerging role of nuclear viral DNA sensors.
Ontology highlight
ABSTRACT:
SUBMITTER: Diner BA
PROVIDER: S-EPMC4646299 | biostudies-literature | 2015 Oct
REPOSITORIES: biostudies-literature
Publications
The emerging role of nuclear viral DNA sensors.
Diner Benjamin A BA Lum Krystal K KK Cristea Ileana M IM
The Journal of biological chemistry 20150909 44
Detecting pathogenic DNA by intracellular receptors termed "sensors" is critical toward galvanizing host immune responses and eliminating microbial infections. Emerging evidence has challenged the dogma that sensing of viral DNA occurs exclusively in sub-cellular compartments normally devoid of cellular DNA. The interferon-inducible protein IFI16 was shown to bind nuclear viral DNA and initiate immune signaling, culminating in antiviral cytokine secretion. Here, we review the newly characterized ...[more]
Similar Datasets
Project description:Viruses are obligatory intracellular parasites and hijack the host cell machinery to make more identical copies of it and continue self-propagation. They attach and replicate in the susceptible and permissive hosts and host derived cell lines. They enter the cells either through direct attachment, receptor-mediated endocytosis, or phagocytosis. Hence, to thwart the invasion by viruses, hosts have developed immunity in ascending stages—intrinsic, innate and adaptive immunity. A robust intrinsic and innate immune response governs an effective adaptive immune response, should that be needed. Both enveloped as well as non-enveloped viruses are subject to distinct types of DNA sensors, subject to their site of replication. DNA sensors of viral PAMPs can be classified into three types, based on the location of their PAMPs in the host cellular compartment viz. cell surface, cytoplasmic and nuclear. The host cell membrane both, surface as well as intra cellular, is continuously monitored for the non-host, pathogenic components or PAMPs. Among the intracellular sensors of the viral genome, there are two types—essentially due to the two types of major viral genomes i.e. RNA and DNA sensors. The cytosolic DNA sensors include AIM2, IFI16, cGAS, RNA Pol III, DNA-PK, DDX9, DHX36, DDX41, DDX60, DAI, LRRFIP1, HMGB, ABCF1 and MRE11. PYHIN family of sensors include AIM2, IFI16, IFIX and MNDA. Another recently discovered family of sensor called stimulator of interferon (IFN) genes (STING), specifically houses on the endoplasmic reticulum (ER) and functions in association with its upstream sensor, cGAS. Some DNA sensors shuttle between the cytosol and nucleus pre- and post-extraneous DNA binding. These include IFI16, IFIX, RNA Pol III, etc. There is no exclusive nuclear DNA sensor. Many enzymes known to be present in the cells for their obvious primary functions also additionally function as DNA sensors. The DNAse family of sensors include DNAse II and TREX1, which are ubiquitously present in the cell for their housekeeping functions. The RNAse family of sensor includes one member—RNA Pol III. Additionally, DNA-PK also functions to cater to viral DNA sensing. The endosomal DNA sensors include TLR7 and TLR9, which belong to the Toll-like receptor (TLR) family. The DExD/H-box helicase family include the putative DNA sensors recently discovered including DDX9, DHX36, DDX41 and DDX60. Several other sensors remain to be characterised or are less classified viz. DAI, LRRFIP1, HMGB, ABCF1, MRE11. In general, response to a viral RNA or DNA produces three types of responses, namely, production of antiviral cytokines including Types I and III IFNs, release of pro-inflammatory and inflammatory cytokines and chemotactic factors. This chapter discusses the structure, function and mechanism of action of the viral DNA sensors explored till date.
| S-EPMC7121249 | biostudies-literature
Project description:RNA sensors detect foreign and endogenous RNAs to protect the host by initiating innate and adaptive immune response. In tumor microenvironment (TME), activation of RNA sensors induces tumor-inhibitory cytotoxic T lymphocyte responses and inhibits the activity of immunosuppressive cells though stimulating type I IFN signaling pathway. These characteristics allow RNA sensors to be prospective targets in tumor immunotherapy. Therefore, a comprehensive understanding of the roles of RNA sensors in TME could provide new insight into the antitumor immunotherapy. Moreover, RNA sensors could be prominent triggering targets to synergize with immunotherapies. In this review, we highlight the diverse mechanisms of RNA sensors in cancer immunity and their emerging contributions in cancer immunotherapy, including monotherapy with RNA sensor agonists, as well as combination with chemotherapy, radiotherapy, immune checkpoint blockade or cancer vaccine.
| S-EPMC9006576 | biostudies-literature
Project description:Viral central nervous system (CNS) infections can lead to life threatening encephalitis and long-term neurological deficits in survivors. Resident CNS cell types, such as astrocytes and microglia, are known to produce key inflammatory and antiviral mediators following infection with neurotropic DNA viruses. However, the mechanisms by which glia mediate such responses remain poorly understood. Recently, a class of intracellular pattern recognition receptors (PRRs), collectively known as DNA sensors, have been identified in both leukocytic and non-leukocytic cell types. The ability of such DNA sensors to initiate immune mediator production and contribute to infection resolution in the periphery is increasingly recognized, but our understanding of their role in the CNS remains limited at best. In this review, we describe the evidence for the expression and functionality of DNA sensors in resident brain cells, with a focus on their role in neurotropic virus infections. The available data indicate that glia and neurons can constitutively express, and/or can be induced to express, various disparate DNA sensing molecules previously described in peripheral cell types. Furthermore, multiple lines of investigation suggest that these sensors are functional in resident CNS cells and are required for innate immune responses to viral infections. However, it is less clear whether DNA sensormediated glial responses are beneficial or detrimental, and the answer to this question appears to dependent on the context of the infection with regard to the identity of the pathogen, host cell type, and host species. Defining such parameters will be essential if we are to successfully target these molecules to limit damaging inflammation while allowing beneficial host responses to improve patient outcomes.
| S-EPMC7525022 | biostudies-literature
Project description:DNA sensors are a core component of innate immunity in mammalian cells. In response to pathogen infection, these specialized proteins sense pathogenic DNA from bacteria or viruses and initiate immune signaling cascades. These defense mechanisms rely on the rapid formation and temporal regulation of protein-protein interactions. Similarly, protein interactions underlie virus immune evasion mechanisms, as proteins from diverse viruses associate with and inhibit DNA sensors. Here, we describe experimental protocols for identifying protein interactions of DNA sensors, and discuss considerations for optimal isolation of protein complexes when targeting either endogenous or tagged proteins. Additionally, as viral infections and immune responses are known to induce prominent changes in cellular protein abundances, we provide a workflow for investigating these protein associations in the context of proteome alterations.
| S-EPMC6889811 | biostudies-literature
Project description:Viruses may exploit the cardiovascular system to facilitate transmission or within-host dissemination, and the symptoms of many viral diseases stem at least in part from a loss of vascular integrity. The microvascular architecture is comprised of an endothelial cell barrier ensheathed by perivascular cells (pericytes). Pericytes are antigen-presenting cells (APCs) and play crucial roles in angiogenesis and the maintenance of microvascular integrity through complex reciprocal contact-mediated and paracrine crosstalk with endothelial cells. We here review the emerging ways that viruses interact with pericytes and pay consideration to how these interactions influence microvascular function and viral pathogenesis. Major outcomes of virus-pericyte interactions include vascular leakage or haemorrhage, organ tropism facilitated by barrier disruption, including viral penetration of the blood-brain barrier and placenta, as well as inflammatory, neurological, cognitive and developmental sequelae. The underlying pathogenic mechanisms may include direct infection of pericytes, pericyte modulation by secreted viral gene products and/or the dysregulation of paracrine signalling from or to pericytes. Viruses we cover include the herpesvirus human cytomegalovirus (HCMV, Human betaherpesvirus 5), the retrovirus human immunodeficiency virus (HIV; causative agent of acquired immunodeficiency syndrome, AIDS, and HIV-associated neurocognitive disorder, HAND), the flaviviruses dengue virus (DENV), Japanese encephalitis virus (JEV) and Zika virus (ZIKV), and the coronavirus severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2; causative agent of coronavirus disease 2019, COVID-19). We touch on promising pericyte-focussed therapies for treating the diseases caused by these important human pathogens, many of which are emerging viruses or are causing new or long-standing global pandemics.
| S-EPMC8513640 | biostudies-literature
Project description:Monitoring kidney transplants for rejection conventionally includes serum creatinine, immunosuppressive drug levels, proteinuria, and donor-specific antibody (DSA). Serum creatinine is a late marker of allograft injury, and the predictive ability of DSA regarding risk of rejection is variable. Histological analysis of an allograft biopsy is the standard method for diagnosing rejection but is invasive, inconvenient, and carries risk of complications. There has been a long quest to find a perfect biomarker that noninvasively predicts tissue injury caused by rejection at an early stage, so that diagnosis and treatment could be pursued without delay in order to minimize irreversible damage to the allograft. In this review, we discuss relatively novel research on identifying biomarkers of tissue injury, specifically elaborating on donor-derived cell-free DNA, and its clinical utility.
| S-EPMC8611196 | biostudies-literature
Project description:Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system. The inflammatory and neurodegenerative pathways driving MS are modulated by DNA, lysine, and arginine methylation, as evidenced by studies made possible by novel tools for methylation detection or loss of function. We present evidence that MS is associated with genetic variants and metabolic changes that impact on methylation. Further, we comprehensively review current understanding of how methylation can impact on central nervous system (CNS) resilience and neuroregenerative potential, as well as inflammatory versus regulatory T helper (Th) cell balance. These findings are discussed in the context of therapeutic relevance for MS, with broad implications in other neurologic and immune-mediated diseases.
| S-EPMC5492960 | biostudies-literature
Project description:Kaposi's sarcoma-associated herpesvirus (KSHV), like other herpesviruses, replicates within the nuclei of its human cell host and hijacks host machinery for expression of its genes. The activities that culminate in viral DNA synthesis and assembly of viral proteins into capsids physically concentrate in nuclear areas termed viral replication compartments. We sought to better understand the spatiotemporal regulation of viral RNAs during the KSHV lytic phase by examining and quantifying the subcellular localization of select viral transcripts. We found that viral mRNAs, as expected, localized to the cytoplasm throughout the lytic phase. However, dependent on active viral DNA replication, viral transcripts also accumulated in the nucleus, often in foci in and around replication compartments, independent of the host shutoff effect. Our data point to involvement of the viral long noncoding polyadenylated nuclear (PAN) RNA in the localization of an early, intronless viral mRNA encoding ORF59-58 to nuclear foci that are associated with replication compartments.IMPORTANCE Late in the lytic phase, mRNAs from Kaposi's sarcoma-associated herpesvirus accumulate in the host cell nucleus near viral replication compartments, centers of viral DNA synthesis and virion production. This work contributes spatiotemporal data on herpesviral mRNAs within the lytic host cell and suggests a mechanism for viral RNA accumulation. Our findings indicate that the mechanism is independent of the host shutoff effect and splicing but dependent on active viral DNA synthesis and in part on the viral noncoding RNA, PAN RNA. PAN RNA is essential for the viral life cycle, and its contribution to the nuclear accumulation of viral messages may facilitate propagation of the virus.
| S-EPMC6002709 | biostudies-literature
Project description:Typical viral propagation involves sequential viral entry, uncoating, replication, gene transcription and protein synthesis, and virion assembly and release. Some viral proteins must be transported into host nucleus to facilitate viral propagation, which is essential for the production of mature virions. During the transport process, nuclear localization signals (NLSs) play an important role in guiding target proteins into nucleus through the nuclear pore. To date, some classical nuclear localization signals (cNLSs) and non-classical NLSs (ncNLSs) have been identified in a number of viral proteins. These proteins are involved in viral replication, expression regulation of viral genes and virion assembly. Moreover, other proteins are transported into nucleus with unknown mechanisms. This review highlights our current knowledge about the nuclear trafficking of cellular proteins associated with viral propagation.
| S-EPMC6893576 | biostudies-literature
Project description:A 10-kb region of the nuclear genome of the yeast Vanderwaltozyma polyspora contains an unusual cluster of five pseudogenes homologous to five different genes from yeast killer viruses, killer plasmids, the 2microm plasmid, and a Penicillium virus. By further database searches, we show that this phenomenon is not unique to V. polyspora but that about 40% of the sequenced genomes of Saccharomycotina species contain integrated copies of genes from DNA plasmids or RNA viruses. We propose the name NUPAVs (nuclear sequences of plasmid and viral origin) for these objects, by analogy to NUMTs (nuclear copies of mitochondrial DNA) and NUPTs (nuclear copies of plastid DNA, in plants) of organellar origin. Although most of the NUPAVs are pseudogenes, one intact and active gene that was formed in this way is the KHS1 chromosomal killer locus of Saccharomyces cerevisiae. We show that KHS1 is a NUPAV related to M2 killer virus double-stranded RNA. Many NUPAVs are located beside tRNA genes, and some contain sequences from a mixture of different extrachromosomal sources. We propose that NUPAVs are sequences that were captured by the nuclear genome during the repair of double-strand breaks that occurred during evolution and that some of their properties may be explained by repeated breakage at fragile chromosomal sites.
| S-EPMC2756859 | biostudies-literature