Negative Regulation of Cytosolic Sensing of DNA

Abe, Takayuki; Shapira, Sagi

doi:10.1016/bs.ircmb.2018.09.002

Cited by 18 publications

(13 citation statements)

References 124 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…129,130 Aside from these, other molecules can directly inhibit binding of MyD88 or TRIF with TLRs or downstream molecules including TRAF3, TRAF6 and TAK1 -summarized in detail elsewhere. 131 Finally, NF-κB signaling can directly be directly suppressed by cl-3, IκBNS, Nurr1, ATF3, and/or PDLIM2. 132 B cells and pDC constitutively express TLR7 and TLR9 and produce large amounts of type I IFNs following exposure to cognate ligands ssRNA and CpG ODN, respectively.…”

Section: Tlr9 Activation and Signaling Pathwaysmentioning

confidence: 99%

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

Karapetyan

Luke

Davar

2020

OTT

View full text Add to dashboard Cite

Toll-like receptor 9 (TLR9) is a pattern recognition receptor that is predominantly located intracellularly in immune cells, including dendritic cells, macrophages, natural killer cells, and other antigen-presenting cells (APC). The primary ligands for TLR9 receptors are unmethylated cytidine phosphate guanosine (CpG) oligodinucleotides (ODN). TLR9 agonists induce inflammatory processes that result in the enhanced uptake and killing of microorganisms and cancer cells as well as the generation of adaptive immune responses. Preclinical studies of TLR9 agonists suggested efficacy both as monotherapy and in combination with several agents, which led to clinical trials in patients with advanced cancer. In these studies, intravenous, intratumoral, and subcutaneous routes of administration have been tested; with anti-tumor responses in both treated and untreated metastatic sites. TLR9 agonist monotherapy is safe, although efficacy is minimal in advanced cancer patients; conversely, combinations appear to be more promising. Several ongoing phase I and II clinical trials are evaluating TLR9 agonists in combination with a variety of agents including chemotherapy, radiotherapy, targeted therapy, and immunotherapy agents. In this review article, we describe the distribution, structure and signaling of TLR9; discuss the results of preclinical studies of TLR9 agonists; and review ongoing clinical trials of TLR9 agonists singly and in combination in patients with advanced solid tumors.

show abstract

Section: Tlr9 Activation and Signaling Pathwaysmentioning

confidence: 99%

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

Karapetyan

Luke

Davar

2020

OTT

View full text Add to dashboard Cite

show abstract

“…[27][28][29][30] Notably, CDN-bound STING also stimulates autophagy, an evolutionarily conserved mechanism for the preservation of cellular and organismal homeostasis, [31][32][33] and such a function appears to be more ancient than the initiation of IRF3 and NF-κB transcriptional activity. 34 STING is particularly prone to activation in the context of viral or bacterial infection, at least in part reflecting (1) the elevated sensitivity of CGAS for histone-free DNA, 35,36 and (2) the direct contribution of bacterial CDNs to STING. 25,26 However, STING can also be triggered by the cytosolic accumulation of endogenous DNA of both nuclear [37][38][39] and more so mitochondrial [40][41][42][43][44] origin.…”

Section: Introductionmentioning

confidence: 99%

Trial watch: STING agonists in cancer therapy

et al. 2020

View full text Add to dashboard Cite

Stimulator of interferon response cGAMP interactor 1 (STING1, best known as STING) is an endoplasmic reticulum-sessile protein that serves as a signaling hub, receiving input from several pattern recognition receptors, most of which sense ectopic DNA species in the cytosol. In particular, STING ensures the production of type I interferon (IFN) in response to invading DNA viruses, bacterial pathogens, as well as DNA leaking from mitochondria or the nucleus (e.g., in cells exposed to chemotherapy or radiotherapy). As a type I IFN is critical for the initiation of anticancer immune responses, the pharmaceutical industry has generated molecules that directly activate STING for use in oncological indications. Such STING agonists are being tested in clinical trials with the rationale of activating STING in tumor cells or tumor-infiltrating immune cells (including dendritic cells) to elicit immunostimulatory effects, alone or in combination with a range of established chemotherapeutic and immunotherapeutic regimens. In this Trial Watch, we discuss preclinical evidence and accumulating clinical experience shaping the design of Phase I and Phase II trials that evaluate the safety and preliminary efficacy of STING agonists in cancer patients.

show abstract

“…First, in the context of CoV infection, intracellular sensing of viral RNA through DDX58 (also known as RIG-I; Retinoic Acid-Inducible Gene I), a pathogen recognition receptor, triggers a signaling cascade that results in the production and secretion of Type I interferons (IFNα/β) 23,24 . IFNα/β in turn binds to cell surface receptors (IFNRs) on nearby cells and, following a signal-transduction cascade, leads to STAT1-mediated ( S ignal T ransducer And A ctivator Of T ranscription 1) upregulation of hundreds of IFN-stimulated genes (ISGs) which govern cellular responses to infection and render cells refractory to viral infection.…”

Section: Resultsmentioning

confidence: 99%

“…IFNα/β in turn binds to cell surface receptors (IFNRs) on nearby cells and, following a signal-transduction cascade, leads to STAT1-mediated ( S ignal T ransducer And A ctivator Of T ranscription 1) upregulation of hundreds of IFN-stimulated genes (ISGs) which govern cellular responses to infection and render cells refractory to viral infection. These responses are indispensable for control of viral replication and initiation of long-term immune responses 23,24 . As shown in Figure 3, we find that NSP13 of CoV mimics DDX3X and RIG-I as well as other helicase proteins, critical cellular components that cooperate through both direct and indirect interactions to initiate immune responses to viral infection.…”

Section: Resultsmentioning

confidence: 99%

“…As shown in Figure 3, we find that NSP13 of CoV mimics DDX3X and RIG-I as well as other helicase proteins, critical cellular components that cooperate through both direct and indirect interactions to initiate immune responses to viral infection. Importantly, RIG-I ligands include ssRNAs that contain a 5’-triphosphate moiety 23,24 and previous biochemical characterizations have attributed multiple enzymatic activities to NSP13, including hydrolysis of NTPs and dNTPs and RNA 5’-triphosphatase activity 25,26 . So, mimicry of RIG-I may serve to reduce the amount of viral RNA that is available to be sensed in infected cells.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

A sweep of earth’s virome reveals host-guided viral protein structural mimicry; with implications for human disease

Lasso

Shapira

2020

Preprint

Self Cite

View full text Add to dashboard Cite

19Viruses deploy an array of genetically encoded strategies to coopt host machinery and support viral 20 replicative cycles. Molecular mimicry, manifested by structural similarity between viral and endogenous 21 host proteins, allow viruses to harness or disrupt cellular functions including nucleic acid metabolism and 22 modulation of immune responses. Here, we use protein structure similarity to scan for virally encoded 23 structure mimics across thousands of catalogued viruses and hosts spanning broad ecological niches and 24 taxonomic range, including bacteria, plants and fungi, invertebrates and vertebrates. Our survey identified 25 over 6,000,000 instances of structural mimicry, the vast majority of which (>70%) cannot be discerned 26 through protein sequence. The results point to molecular mimicry as a pervasive strategy employed by 27 viruses and indicate that the protein structure space used by a given virus is dictated by the host proteome. 28Interrogation of proteins mimicked by human-infecting viruses points to broad diversification of cellular 29 pathways targeted via structural mimicry, identifies biological processes that may underly autoimmune 30 disorders, and reveals virally encoded mimics that may be leveraged to engineer synthetic metabolic circuits 31 or may serve as targets for therapeutics. Moreover, the manner and degree to which viruses exploit 32 molecular mimicry varies by genome size and nucleic acid type, with ssRNA viruses circumventing 33 limitations of their small genomes by mimicking human proteins to a greater extent than their large dsDNA 34 counterparts. Finally, we identified over 140 cellular proteins that are mimicked by CoV, providing clues 35 about cellular processes driving the pathogenesis of the ongoing COVID-19 pandemic.36 37 42 structure-informed prediction algorithms have allowed discovery of such interactions across all fully 43 sequenced human infecting viruses 1 . Molecular mimicry, manifested by structural similarity between viral 44 and endogenous host proteins, allow viruses to harness or disrupt cellular functions including nucleic acid 45 metabolism and modulation of immune responses. Yet, while examples of this latter strategy pepper the 46 literature 2-4 , most have focused on human infecting viruses 5,6 and a systematic analysis of pathogen-encoded 47 molecular mimics has not been performed. 49The vast genomic landscape occupied by viruses hampers the discovery of evolutionary relationships 50 between viral proteins and their hosts. As is well known however, since 3-dimensional (3D) protein 51 structure is much better conserved than sequence, structural information can be used to interrogate 52 3 evolutionary relationships 1,7 as well as uncover virus-encoded structural mimics that cannot be detected by 53 sequence relationships (see Methods). Here, we use protein structure similarity to identify virally encoded 54 mimics of host proteomes. Briefly, we first employ sequence-based methods to identify proteins that have 55 similar structures to queried viral ...

show abstract

Negative Regulation of Cytosolic Sensing of DNA

Cited by 18 publications

References 124 publications

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

<p>Toll-Like Receptor 9 Agonists in Cancer</p>

Trial watch: STING agonists in cancer therapy

A sweep of earth’s virome reveals host-guided viral protein structural mimicry; with implications for human disease

Contact Info

Product

Resources

About