Nucleic acids and endosomal pattern recognition: how to tell friend from foe?

Brencicova, Eva; Diebold, Sandra S.

doi:10.3389/fcimb.2013.00037

Cited by 102 publications

(104 citation statements)

References 145 publications

(163 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…An upstream regulator analysis algorithm also identified activation of the immune system and cell‐mediated immune responses in the development of DGF. The main “drivers” within these processes, typically related to the response to pathogens (bacterial and viral), or sterile inflammation and induction of the secondary INF‐γ‐associated responses to dsRNA, which have been linked to mechanisms underpinning autoimmune diseases (Brencicova & Diebold, 2013; Nellimarla & Mossman, 2014; Pollard, Cauvi, Toomey, Morris, & Kono, 2013) and cellular ageing (Gorbunova, Boeke, Helfand, & Sedivy, 2014). …”

Section: Resultsmentioning

confidence: 99%

A molecular signature for delayed graft function

et al. 2018

View full text Add to dashboard Cite

Chronic kidney disease and associated comorbidities (diabetes, cardiovascular diseases) manifest with an accelerated ageing phenotype, leading ultimately to organ failure and renal replacement therapy. This process can be modulated by epigenetic and environmental factors which promote loss of physiological function and resilience to stress earlier, linking biological age with adverse outcomes post‐transplantation including delayed graft function (DGF). The molecular features underpinning this have yet to be fully elucidated. We have determined a molecular signature for loss of resilience and impaired physiological function, via a synchronous genome, transcriptome and proteome snapshot, using human renal allografts as a source of healthy tissue as an in vivo model of ageing in humans. This comprises 42 specific transcripts, related through IFNγ signalling, which in allografts displaying clinically impaired physiological function (DGF) exhibited a greater magnitude of change in transcriptional amplitude and elevated expression of noncoding RNAs and pseudogenes, consistent with increased allostatic load. This was accompanied by increased DNA methylation within the promoter and intragenic regions of the DGF panel in preperfusion allografts with immediate graft function. Pathway analysis indicated that an inability to sufficiently resolve inflammatory responses was enabled by decreased resilience to stress and resulted in impaired physiological function in biologically older allografts. Cross‐comparison with publically available data sets for renal pathologies identified significant transcriptional commonality for over 20 DGF transcripts. Our data are clinically relevant and important, as they provide a clear molecular signature for the burden of “wear and tear” within the kidney and thus age‐related physiological capability and resilience.

show abstract

Section: Resultsmentioning

confidence: 99%

A molecular signature for delayed graft function

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Unlike viral RNAs, which are distinct from cellular RNAs and therefore recognized by intracellular PRRs, DNA genomes of viruses that replicate in the nucleus are thought to be chemically and structurally similar to host DNA (2)(3)(4). It was therefore generally accepted that viral DNA sensing was limited to the cytoplasm where aberrant DNA accumulation would be perceived as "foreign."…”

Section: Virus-host Interactionsmentioning

confidence: 99%

cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection

Orzalli

Broekema

Diner

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

211

225

View full text Add to dashboard Cite

Interferon γ-inducible protein 16 (IFI16) and cGMP-AMP synthase (cGAS) have both been proposed to detect herpesviral DNA directly in herpes simplex virus (HSV)-infected cells and initiate interferon regulatory factor-3 signaling, but it has been unclear how two DNA sensors could both be required for this response. We therefore investigated their relative roles in human foreskin fibroblasts (HFFs) infected with HSV or transfected with plasmid DNA. siRNA depletion studies showed that both are required for the production of IFN in infected HFFs. We found that cGAS shows low production of cGMP-AMP in infected cells, but instead cGAS is partially nuclear in normal human fibroblasts and keratinocytes, interacts with IFI16 in fibroblasts, and promotes the stability of IFI16. IFI16 is associated with viral DNA and targets to viral genome complexes, consistent with it interacting directly with viral DNA. Our results demonstrate that IFI16 and cGAS cooperate in a novel way to sense nuclear herpesviral DNA and initiate innate signaling.protein-protein interactions | DNA sensing | innate immunity | virus-host interactions T he innate immune response is a crucial component of host immunity and is the first line of defense against microbial pathogens, including bacteria and viruses. The initial events during infection of a host cell induce intracellular signaling pathways, resulting in the production of proinflammatory cytokines and IFNs. These effector molecules activate an antiviral state in neighboring cells and recruit immune cells to promote clearance of infection. Viral nucleic acids are potent activators of these signaling pathways and are recognized by a subset of host cell pattern recognition receptors (PRRs). These PRRs include the membrane-bound Toll-like receptors, the cytosolic RIG-Ilike receptors, and a broad class of putative DNA sensors, which include both cytosolic and nuclear proteins (1).Unlike viral RNAs, which are distinct from cellular RNAs and therefore recognized by intracellular PRRs, DNA genomes of viruses that replicate in the nucleus are thought to be chemically and structurally similar to host DNA (2-4). It was therefore generally accepted that viral DNA sensing was limited to the cytoplasm where aberrant DNA accumulation would be perceived as "foreign." However, this dogma has recently been challenged by the identification of DNA-sensing pathways that are active in the nucleus. The Pyrin and HIN-containing interferon γ-inducible protein 16 (IFI16) protein, initially described as a cytosolic DNA sensor (5), has been demonstrated to be nuclear in many cells and to promote the activation of inflammasomes (6, 7) and production of IFNs (8, 9) in response to herpesvirus infection. These initial studies involved short-term siRNA depletion of IFI16; in addition, a recent study showed that long-term knockdown of IFI16 expression led to abrogated IFN responses to not only DNA viruses, such as herpes simplex virus (HSV), but also RNA viruses, such as Sendai virus (10).cGMP-AMP synthase (cGAS) was also ident...

show abstract

“…The nucleic acids derived from viruses during cytosolic replication can be transported into endosomes via autophagy. The expression of these TLRs in intracellular compartments prevents the activation of these TLRs by self-derived nucleic acids under physiological conditions because self-nucleic acids from dead cells within damaged tissues are unable to enter the cells and endosomes spontaneously (22,23). However, self-nucleic acid tolerance can be broken under some pathological conditions.…”

mentioning

confidence: 99%

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7–9

Lai

Yeh

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Activation of TLR7–9 has been linked to the pathogenesis of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and psoriasis. Thus, therapeutic applications of antagonists of these TLRs for such disorders are being investigated. Bortezomib (Velcade) is a proteasome inhibitor known to suppress activation of these TLRs. To identify novel TLR7–9 inhibitors, we searched the Gene Expression Omnibus database for gene expression profiles of bortezomib-treated cells. These profiles were then used to screen the Connectivity Map database for chemical compounds with similar functions as bortezomib. A natural antibiotic, thiostrepton, was identified for study. Similar to bortezomib, thiostrepton effectively inhibits TLR7–9 activation in cell-based assays and in dendritic cells. In contrast to bortezomib, thiostrepton does not inhibit NF-κB activation induced by TNF-α, IL-1, and other TLRs, and it is less cytotoxic to dendritic cells. Thiostrepton inhibits TLR9 localization in endosomes for activation via two mechanisms, which distinguish it from currently used TLR7–9 inhibitors. One mechanism is similar to the proteasome inhibitory function of bortezomib, whereas the other is through inhibition of endosomal acidification. Accordingly, in different animal models, thiostrepton attenuated LL37- and imiquimod-induced psoriasis-like inflammation. These results indicated that thiostrepton is a novel TLR7–9 inhibitor, and compared with bortezomib, its inhibitory effect is more specific to these TLRs, suggesting the potential therapeutic applications of thiostrepton on immunologic disorders elicited by inappropriate activation of TLR7–9.

show abstract

Nucleic acids and endosomal pattern recognition: how to tell friend from foe?

Cited by 102 publications

References 145 publications

A molecular signature for delayed graft function

A molecular signature for delayed graft function

cGAS-mediated stabilization of IFI16 promotes innate signaling during herpes simplex virus infection

Identification of Thiostrepton as a Novel Inhibitor for Psoriasis-like Inflammation Induced by TLR7–9

Contact Info

Product

Resources

About