scholarly journals Cyclic GMP-AMP Synthase Is an Innate Immune Sensor of HIV and Other Retroviruses

Science ◽  
2013 ◽  
Vol 341 (6148) ◽  
pp. 903-906 ◽  
Author(s):  
Daxing Gao ◽  
Jiaxi Wu ◽  
You-Tong Wu ◽  
Fenghe Du ◽  
Chukwuemika Aroh ◽  
...  
Keyword(s):  
Leukemia Virus ◽  
Adaptor Protein ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Innate Immune ◽  
Guanosine Monophosphate ◽  
Type I Interferons ◽  
Type I ◽  
Innate Immune Responses ◽  
Hiv Reverse Transcriptase

Retroviruses, including HIV, can activate innate immune responses, but the host sensors for retroviruses are largely unknown. Here we show that HIV infection activates cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) to produce cGAMP, which binds to and activates the adaptor protein STING to induce type I interferons and other cytokines. Inhibitors of HIV reverse transcriptase, but not integrase, abrogated interferon-β induction by the virus, suggesting that the reverse-transcribed HIV DNA triggers the innate immune response. Knockout or knockdown of cGAS in mouse or human cell lines blocked cytokine induction by HIV, murine leukemia virus, and simian immunodeficiency virus. These results indicate that cGAS is an innate immune sensor of HIV and other retroviruses.

scholarly journals A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Daipayan Banerjee ◽  
Kurt Langberg ◽  
Salar Abbas ◽  
Eric Odermatt ◽  
Praveen Yerramothu ◽  
...  
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Signal Transduction Pathway ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Type I Interferons ◽  
Type I ◽  
Dependent Manner ◽  
Damage Response

AbstractCyclic guanosine monophosphate-adenosine monophosphate (cGAMP), produced by cyclic GMP-AMP synthase (cGAS), stimulates the production of type I interferons (IFN). Here we show that cGAMP activates DNA damage response (DDR) signaling independently of its canonical IFN pathways. Loss of cGAS dampens DDR signaling induced by genotoxic insults. Mechanistically, cGAS activates DDR in a STING-TBK1-dependent manner, wherein TBK1 stimulates the autophosphorylation of the DDR kinase ATM, with the consequent activation of the CHK2-p53-p21 signal transduction pathway and the induction of G1 cell cycle arrest. Despite its stimulatory activity on ATM, cGAMP suppresses homology-directed repair (HDR) through the inhibition of polyADP-ribosylation (PARylation), in which cGAMP reduces cellular levels of NAD+; meanwhile, restoring NAD+ levels abrogates cGAMP-mediated suppression of PARylation and HDR. Finally, we show that cGAMP also activates DDR signaling in invertebrate species lacking IFN (Crassostrea virginica and Nematostella vectensis), suggesting that the genome surveillance mechanism of cGAS predates metazoan interferon-based immunity.

scholarly journals TBK1 recruitment to STING activates both IRF3 and NF-κB that mediate immune defense against tumors and viral infections

2021 ◽  
Vol 118 (14) ◽  
pp. e2100225118
Author(s):  
Seoyun Yum ◽  
Minghao Li ◽  
Yan Fang ◽  
Zhijian J. Chen
Keyword(s):  
Viral Infections ◽  
Adenosine Monophosphate ◽  
Nuclear Factor Κb ◽  
Cyclic Guanosine Monophosphate ◽  
Immune Defense ◽  
Guanosine Monophosphate ◽  
Type I Interferons ◽  
Type I ◽  
Autophagy Induction ◽  
Independent Functions

The induction of type I interferons through the transcription factor interferon regulatory factor 3 (IRF3) is considered a major outcome of stimulator of interferon genes (STING) activation that drives immune responses against DNA viruses and tumors. However, STING activation can also trigger other downstream pathways such as nuclear factor κB (NF-κB) signaling and autophagy, and the roles of interferon (IFN)-independent functions of STING in infectious diseases or cancer are not well understood. Here, we generated a STING mouse strain with a mutation (S365A) that disrupts IRF3 binding and therefore type I interferon induction but not NF-κB activation or autophagy induction. We also generated STING mice with mutations that disrupt the recruitment of TANK-binding kinase 1 (TBK1), which is important for both IRF3 and NF-κB activation but not autophagy induction (L373A or ∆CTT, which lacks the C-terminal tail). The STING-S365A mutant mice, but not L373A or ∆CTT mice, were still resistant to herpes simplex virus 1 (HSV-1) infections and mounted an antitumor response after cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) treatment despite the absence of STING-induced interferons. These results demonstrate that STING can function independently of type I interferons and autophagy, and that TBK1 recruitment to STING is essential for antiviral and antitumor immunity.

scholarly journals An inhalable nanoparticulate STING agonist synergizes with radiotherapy to confer long-term control of lung metastases

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Yang Liu ◽  
William N. Crowe ◽  
Lulu Wang ◽  
Yong Lu ◽  
W. Jeffrey Petty ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Lung Metastases ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Type I Interferons ◽  
Type I ◽  
Term Survival ◽  
Anticancer Immunity

Abstract Mounting evidence suggests that the tumor microenvironment is profoundly immunosuppressive. Thus, mitigating tumor immunosuppression is crucial for inducing sustained antitumor immunity. Whereas previous studies involved intratumoral injection, we report here an inhalable nanoparticle-immunotherapy system targeting pulmonary antigen presenting cells (APCs) to enhance anticancer immunity against lung metastases. Inhalation of phosphatidylserine coated liposome loaded with STING agonist cyclic guanosine monophosphate–adenosine monophosphate (NP-cGAMP) in mouse models of lung metastases enables rapid distribution of NP-cGAMP to both lungs and subsequent uptake by APCs without causing immunopathology. NP-cGAMP designed for enhanced cytosolic release of cGAMP stimulates STING signaling and type I interferons production in APCs, resulting in the pro-inflammatory tumor microenvironment in multifocal lung metastases. Furthermore, fractionated radiation delivered to one tumor-bearing lung synergizes with inhaled NP-cGAMP, eliciting systemic anticancer immunity, controlling metastases in both lungs, and conferring long-term survival in mice with lung metastases and with repeated tumor challenge.

scholarly journals Regulation of TRIF-mediated innate immune response by K27-linked polyubiquitination and deubiquitination

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Xin Wu ◽  
Caoqi Lei ◽  
Tian Xia ◽  
Xuan Zhong ◽  
Qing Yang ◽  
...  
Keyword(s):  
Immune Responses ◽  
Adaptor Protein ◽  
Innate Immune ◽  
Negative Regulator ◽  
Type I Interferons ◽  
Poly I:C ◽  
Type I ◽  
Innate Immune Responses

Abstract TIR domain-containing adaptor inducing interferon-β (TRIF) is an essential adaptor protein required for innate immune responses mediated by Toll-like receptor (TLR) 3- and TLR4. Here we identify USP19 as a negative regulator of TLR3/4-mediated signaling. USP19 deficiency increases the production of type I interferons (IFN) and proinflammatory cytokines induced by poly(I:C) or LPS in vitro and in vivo. Usp19-/- mice have more serious inflammation after poly(I:C) or LPS treatment, and are more susceptible to inflammatory damages and death following Salmonella typhimurium infection. Mechanistically, USP19 interacts with TRIF and catalyzes the removal of TRIF K27-linked polyubiquitin moieties, thereby impairing the recruitment of TRIF to TLR3/4. In addition, the RING E3 ubiquitin ligase complex Cullin-3-Rbx1-KCTD10 catalyzes K27-linked polyubiquitination of TRIF at K523, and deficiency of this complex inhibits TLR3/4-mediated innate immune signaling. Our findings thus reveal TRIF K27-linked polyubiquitination and deubiquitination as a critical regulatory mechanism of TLR3/4-mediated innate immune responses.

scholarly journals Brucella spp. Omp25 Promotes Proteasome-Mediated cGAS Degradation to Attenuate IFN-β Production

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruizhen Li ◽  
Wenli Liu ◽  
Xiangrui Yin ◽  
Fangfang Zheng ◽  
Zhenyu Wang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Pseudorabies Virus ◽  
Mononuclear Cells ◽  
Nuclear Translocation ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Type I Interferons ◽  
Type I ◽  
Regulatory Factor

Type I interferons (IFN), a family of cytokines widely expressed in various tissues, play important roles in anti-infection immunity. Nevertheless, it is not known whether Brucella spp. could interfere with IFN-I production induced by other pathogens. This study investigated the regulatory roles of Brucella outer membrane protein (Omp)25 on the IFN-I signaling pathway and found that Omp25 inhibited the production of IFN-β and its downstream IFN-stimulated genes induced by various DNA viruses or IFN-stimulatory DNA in human, murine, porcine, bovine, and ovine monocyte/macrophages or peripheral blood mononuclear cells. Brucella Omp25 suppressed the phosphorylation of stimulator of IFN genes (STINGs) and IFN regulatory factor 3 and nuclear translocation of phosphorylated IFN regulatory factor 3 in pseudorabies virus- or herpes simplex virus-1-infected murine, human, or porcine macrophages. Furthermore, we found that Brucella Omp25 promoted cyclic guanosine monophosphate–adenosine monophosphate synthase (cGAS) degradation via the proteasome-dependent pathway, resulting in a decreased cyclic guanosine monophosphate–adenosine monophosphate production and downstream signaling activation upon DNA virus infection or IFN-stimulatory DNA stimulation. Mapping the predominant function domain of Omp25 showed that the amino acids 161 to 184 of Omp25 were required for Omp25-induced cGAS degradation, among which five amino acid residues (R176, Y179, R180, Y181, and Y184) were required for the inhibitory effect of Omp25 on IFN-β induction. Altogether, our results demonstrated that Brucella Omp25 inhibits cGAS STING signaling pathway-induced IFN-β via facilitating the ubiquitin–proteasome-dependent degradation of cGAS in various mammalian monocyte/macrophages.

scholarly journals Cyclic Guanosine Monophosphate–Adenosine Monophosphate Synthase (cGAS), a Multifaceted Platform of Intracellular DNA Sensing

2021 ◽  
Vol 12 ◽  
Author(s):  
Eloi R. Verrier ◽  
Christelle Langevin
Keyword(s):  
Nucleic Acid ◽  
Current Knowledge ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Innate Immune ◽  
Guanosine Monophosphate ◽  
Type I ◽  
Nucleic Acid Binding ◽  
Sting Pathway ◽  
Molecular Patterns

Innate immune pathways are the first line of cellular defense against pathogen infections ranging from bacteria to Metazoa. These pathways are activated following the recognition of pathogen associated molecular patterns (PAMPs) by membrane and cytosolic pattern recognition receptors. In addition, some of these cellular sensors can also recognize endogenous danger-associated molecular patterns (DAMPs) arising from damaged or dying cells and triggering innate immune responses. Among the cytosolic nucleic acid sensors, the cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) synthase (cGAS) plays an essential role in the activation of the type I interferon (IFNs) response and the production of pro-inflammatory cytokines. Indeed, upon nucleic acid binding, cGAS synthesizes cGAMP, a second messenger mediating the activation of the STING signaling pathway. The functional conservation of the cGAS-STING pathway during evolution highlights its importance in host cellular surveillance against pathogen infections. Apart from their functions in immunity, cGAS and STING also play major roles in nuclear functions and tumor development. Therefore, cGAS-STING is now considered as an attractive target to identify novel biomarkers and design therapeutics for auto-inflammatory and autoimmune disorders as well as infectious diseases and cancer. Here, we review the current knowledge about the structure of cGAS and the evolution from bacteria to Metazoa and present its main functions in defense against pathogens and cancer, in connection with STING. The advantages and limitations of in vivo models relevant for studying the cGAS-STING pathway will be discussed for the notion of species specificity and in the context of their integration into therapeutic screening assays targeting cGAG and/or STING.

scholarly journals Crosstalk Between Autophagy and the cGAS–STING Signaling Pathway in Type I Interferon Production

2021 ◽  
Vol 9 ◽  
Author(s):  
Kunli Zhang ◽  
Sutian Wang ◽  
Hongchao Gou ◽  
Jianfeng Zhang ◽  
Chunling Li
Keyword(s):  
Signaling Pathway ◽  
Adenosine Monophosphate ◽  
Degradation Process ◽  
Guanosine Monophosphate ◽  
Type I Interferons ◽  
Research Progress ◽  
Type I ◽  
Type I Ifn ◽  
Major Pathway ◽  
Sting Pathway

Innate immunity is the front-line defense against infectious microorganisms, including viruses and bacteria. Type I interferons are pleiotropic cytokines that perform antiviral, antiproliferative, and immunomodulatory functions in cells. The cGAS–STING pathway, comprising the main DNA sensor cyclic guanosine monophosphate/adenosine monophosphate synthase (cGAS) and stimulator of IFN genes (STING), is a major pathway that mediates immune reactions and is involved in the strong induction of type I IFN production, which can fight against microbial infections. Autophagy is an evolutionarily conserved degradation process that is required to maintain host health and facilitate capture and elimination of invading pathogens by the immune system. Mounting evidence indicates that autophagy plays an important role in cGAS–STING signaling pathway-mediated type I IFN production. This review briefly summarizes the research progress on how autophagy regulates the cGAS–STING pathway, regulating type I IFN production, with a particular focus on the crosstalk between autophagy and cGAS–STING signaling during infection by pathogenic microorganisms.

scholarly journals A host type I interferon response is induced by cytosolic sensing of the bacterial second messenger cyclic-di-GMP

2009 ◽  
Vol 206 (9) ◽  
pp. 1899-1911 ◽  
Author(s):  
Sarah M. McWhirter ◽  
Roman Barbalat ◽  
Kathryn M. Monroe ◽  
Mary F. Fontana ◽  
Mamoru Hyodo ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Map Kinases ◽  
Second Messenger ◽  
Innate Immune ◽  
Guanosine Monophosphate ◽  
Host Cells ◽  
Type I Interferons ◽  
Interferon Response ◽  
Type I

The innate immune system responds to unique molecular signatures that are widely conserved among microbes but that are not normally present in host cells. Compounds that stimulate innate immune pathways may be valuable in the design of novel adjuvants, vaccines, and other immunotherapeutics. The cyclic dinucleotide cyclic-di–guanosine monophosphate (c-di-GMP) is a recently appreciated second messenger that plays critical regulatory roles in many species of bacteria but is not produced by eukaryotic cells. In vivo and in vitro studies have previously suggested that c-di-GMP is a potent immunostimulatory compound recognized by mouse and human cells. We provide evidence that c-di-GMP is sensed in the cytosol of mammalian cells via a novel immunosurveillance pathway. The potency of cytosolic signaling induced by c-di-GMP is comparable to that induced by cytosolic delivery of DNA, and both nucleic acids induce a similar transcriptional profile, including triggering of type I interferons and coregulated genes via induction of TBK1, IRF3, nuclear factor κB, and MAP kinases. However, the cytosolic pathway that senses c-di-GMP appears to be distinct from all known nucleic acid–sensing pathways. Our results suggest a novel mechanism by which host cells can induce an inflammatory response to a widely produced bacterial ligand.

scholarly journals Cytosolic DNA sensor-initiated innate immune responses in mouse ovarian granulosa cells

Reproduction ◽  
2017 ◽  
Vol 153 (6) ◽  
pp. 821-834 ◽  
Author(s):  
Keqin Yan ◽  
Dingqing Feng ◽  
Jing Liang ◽  
Qing Wang ◽  
Lin Deng ◽  
...  
Keyword(s):  
Immune Responses ◽  
Granulosa Cells ◽  
Innate Immune ◽  
Type I Interferons ◽  
Endocrine Function ◽  
Type I ◽  
Dna Sensor ◽  
Innate Immune Responses ◽  
Oligoadenylate Synthetase ◽  
Ovarian Granulosa Cells

Viral infections of the ovary may perturb ovarian functions. However, the mechanisms underlying innate immune responses in the ovary are poorly understood. The present study demonstrates that cytosolic viral DNA sensor signaling initiates the innate immune response in mouse ovarian granulosa cells and affects endocrine function. The cytosolic DNA sensors p204 and cGAS and their common signaling adaptor stimulator of interferon (IFN) genes (STING) were constitutively expressed in granulosa cells. Transfection with VACV70, a synthetic vaccinia virus (VACV) DNA analog, induced the expression of type I interferons (IFNA/B) and major inflammatory cytokines (TNFA and IL6) through IRF3 and NF-κB activation respectively. Moreover, several IFN-inducible antiviral proteins, including 2′,5′-oligoadenylate synthetase, IFN-stimulating gene 15 and Mx GTPase 1, were also induced by VACV70 transfection. The innate immune responses in granulosa cells were significantly reduced by the transfection of specific small-interfering RNAs targeting p204, cGas or Sting. Notably, the VACV70-triggered innate immune responses affected steroidogenesis in vivo and in vitro. The data presented in this study describe the mechanism underlying ovarian immune responses to viral infection.

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