HMGB proteins function as universal sentinels for nucleic-acid-mediated innate immune responses

Nature ◽  
2009 ◽  
Vol 462 (7269) ◽  
pp. 99-103 ◽  
Author(s):  
Hideyuki Yanai ◽  
Tatsuma Ban ◽  
ZhiChao Wang ◽  
Myoung Kwon Choi ◽  
Takeshi Kawamura ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Immune Responses ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Hmgb Proteins

scholarly journals DDIS-03. DEVELOPMENT OF A NOVEL CLASS OF cGAS AGONISTS TO TRIGGER STING PATHWAY-DEPENDENT INNATE IMMUNE RESPONSES AGAINST GLIOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi65-vi65
Author(s):  
Alexander Stegh
Keyword(s):  
Nucleic Acid ◽  
Immune Responses ◽  
High Surface ◽  
Innate Immune ◽  
Limiting Factors ◽  
Innate Immune Responses ◽  
Protein Marker ◽  
M1 Macrophage ◽  
Sting Pathway

Abstract The Stimulator of Interferon Genes (STING) pathway represents a major innate immune sensing mechanism for tumor-derived DNA. Modified cyclic dinucleotides (CDNs) that mimic the endogenous STING ligand cGAMP are currently being explored in patients with solid tumors that amenable to intratumoral delivery. Inadequate bioavailability and insufficient lipophilicity are limiting factors for clinical CDN development, in particular when consideration is given to systemic administration approaches. We have shown that the formulation of oligonucleotides into Spherical Nucleic Acid (SNA) nanostructures, i.e., the presentation of oligonucleotides at high density on the surface of nanoparticle cores, lead to biochemical and biological properties that are radically different from those of linear oligonucleotides. First-generation SNAs conjugated with TLR9-agonsitic DNA oligonculeotides (NCT03086278; solid cancers) and intravenously administered, brain-penetrant siRNA-based SNAs (NCT03020017, recurrent GBM) have recently entered clinical trials. Here, we report the development of a STING-agonistic immunotherapy by targeting cGAS, the sensor of cytosolic dsDNA upstream of STING, with SNAs presenting dsDNA at high surface density. The strategy of using SNAs exploits the ability of cGAS to raise STING responses by delivering dsDNA and inducing the catalytic production of endogenous CDNs. SNA nanostructures carrying a 45bp IFN-simulating dsDNA oligonucleotide, the most commonly used and widely characterized cGAS activator, potently activated the cGAS-STING pathway, as evidenced by increased IRF responses, elevated protein marker expression indicative of the activated M1 macrophage state, and enhanced expression of pro-inflammatory cytokines in macrophage cultures in vitro, and in intracranial isogenic GBM explants in vivo. Our use of SNAs addresses the challenges of nucleic acid delivery to intracranial tumor sites, exploits the binding of closely-spaced, neighboring dsDNA molecules on the SNA surface to enhance the formation of a dimeric cGAS:DNA complex, and establishes cGAS-agonistic SNAs as a novel class of immune-stimulatory modalities for triggering innate immune responses against tumor.

scholarly journals Dynamic control of nucleic-acid-sensing Toll-like receptors by the endosomal compartment

2021 ◽  
Author(s):  
Kensuke Miyake ◽  
Shin-ichiroh Saitoh ◽  
Ryutaro Fukui ◽  
Takuma Shibata ◽  
Ryota Sato ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Immune Responses ◽  
Degradation Products ◽  
Proteolytic Cleavage ◽  
Innate Immune ◽  
Cell Periphery ◽  
Type I ◽  
Innate Immune Responses ◽  
Toll Like Receptors ◽  
Endosomal Compartment

Abstract Nucleic acid (NA)-sensing Toll-like receptors (TLRs) are synthesized in the endoplasmic reticulum and mature with chaperones, such as Unc93B1 and the protein associated with TLR4 A (PRAT4A)–gp96 complex. The TLR–Unc93B1 complexes move to the endosomal compartment, where proteases such as cathepsins activate their responsiveness through proteolytic cleavage of the extracellular domain of TLRs. Without proteolytic cleavage, ligand-dependent dimerization of NA-sensing TLRs is prevented by the uncleaved loop in the extracellular domains. Additionally, the association of Unc93B1 inhibits ligand-dependent dimerization of TLR3 and TLR9 and, therefore, Unc93B1 is released from these TLRs before dimerization. Ligand-activated NA-sensing TLRs induce the production of proinflammatory cytokines and act on the endosomal compartment to initiate anterograde trafficking to the cell periphery for type I interferon production. In the endosomal compartment, DNA and RNA are degraded by DNases and RNases, respectively, generating degradation products. DNase 2A and RNase T2 generate ligands for TLR9 and TLR8, respectively. In this mechanism, DNases and RNases control innate immune responses to NAs in endosomal compartments. NA-sensing TLRs and the endosomal compartment work together to monitor environmental cues through endosomes and decide to launch innate immune responses.

scholarly journals DDX41 recognizes RNA/DNA retroviral reverse transcripts and is critical forin vivocontrol of MLV infection

2018 ◽  
Author(s):  
Spyridon Stavrou ◽  
Alexya Aguilera ◽  
Kristin Blouch ◽  
Susan R. Ross
Keyword(s):  
Immune Response ◽  
Nucleic Acid ◽  
Immune Responses ◽  
Innate Immune Response ◽  
Reverse Transcription ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
Retroviral Infection ◽  
Double Stranded Dna

AbstractHost recognition of viral nucleic acids generated during infection leads to the activation of innate immune responses essential for early control of virus. Retrovirus reverse transcription creates numerous potential ligands for cytosolic host sensors that recognize foreign nucleic acids, including single-stranded RNA (ssRNA), RNA/DNA hybrids and double stranded DNA (dsDNA). We and others recently showed that the sensors cyclic GMP-AMP synthase (cGAS), dead-box helicase 41 (DDX41) and members of the Aim2-like receptor (ALR) family participate in the recognition of retroviral reverse transcripts. However, why multiple sensors might be required and their relative importance inin vivocontrol of retroviral infection is not known. Here we show that DDX41 primarily senses the DNA/RNA hybrid generated at the first step of reverse transcription, while cGAS recognizes dsDNA generated at the next step. We also show that both DDX41 and cGAS are needed for the anti-retroviral innate immune response to MLV and HIV in primary mouse macrophages and dendritic cells (DC). Using mice with macrophage- or -specific knockout of the DDX41 gene, we show that DDX41 sensing in DCs but not macrophages was critical for controllingin vivoMLV infection. This suggests that DCs are essentialin vivotargets for infection, as well as for initiating the antiviral response. Our work demonstrates that the innate immune response to retrovirus infection depends on multiple host nucleic acid sensors that recognize different reverse transcription intermediates.ImportanceViruses are detected by many different host sensors of nucleic acid, which in turn trigger innate immune responses, such as type I IFN production, required to control infection. We show here that at least two sensors are needed to initiate a highly effective innate immune response to retroviruses – DDX41, which preferentially senses the RNA/DNA hybrid generated at the first step of retrovirus replication and cGAS, which recognizes double-stranded DNA generated at the 2ndstep. Importantly, we demonstrate using mice lacking DDX41 or cGAS, that both sensors are needed for the full antiviral response needed to controlin vivoMLV infection. These findings underscore the need for multiple host factors to counteract retroviral infection.

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