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β-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion

ABSTRACT: Virus infection may induce excessive interferon (IFN) responses that can lead to host tissue injury or even death. β-arrestin 2 regulates multiple cellular events through the G protein-coupled receptor (GPCR) signaling pathways. Here we demonstrate that β-arrestin 2 also promotes virus-induced production of IFN-β and clearance of viruses in macrophages. β-arrestin 2 interacts with cyclic GMP-AMP synthase (cGAS) and increases the binding of dsDNA to cGAS to enhance cyclic GMP-AMP (cGAMP) production and the downstreatm stimulator of interferon genes (STING) and innate immune responses. Mechanistically, deacetylation of β-arrestin 2 at Lys171 facilitates the activation of the cGAS–STING signaling and the production of IFN-β. In vitro, viral infection induces the degradation of β-arrestin 2 to facilitate immune evasion, while a β-blocker, carvedilol, rescues β-arrestin 2 expression to maintain the antiviral immune response. Our results thus identify a viral immune-evasion pathway via the degradation of β-arrestin 2, and also hint that carvedilol, approved for treating heart failure, can potentially be repurposed as an antiviral drug candidate.

ORGANISM(S): Mus musculus

PROVIDER: GSE159735 | GEO | 2020/10/22

REPOSITORIES: GEO

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An HIV protein mediates immune evasion by targeting cGAS–STING signaling

Project description:The cyclic GMP-AMP synthase (cGAS) recognizes Y-form cDNA of HIV-1 and initiate the antiviral immune response through cGAS–STING–TBK1–IRF3–type I IFN (IFN-I) signaling cascade. HIV-1 uses several strategies to interfere with the host immune molecules and mediate immune evasion. However, the potential role of HIV-1 proteins in cGAS–STING signaling remains unclear. Here we report that the HIV-1 protein p6 suppresses HIV-1-stimulated expression of IFN-I and promotes the immune evasion. Mechanistically, p6 bound with STING and inhibited the activation of STING and the interaction between STING and TBK1. Moreover, the glutamylation of p6 at Glu6 residue inhibited the interaction between STING and TRIM32 or AMFR, which subsequently suppressed the K27- and K63-linked polyubiquitination of STING at Lys337, therefore inhibited STING activation and type I IFN production, while the mutation of Glu6 residue lost the inhibitory effect. However, CoCl2, an agonist for cytosolic carboxypeptidases (CCPs), counteracted the glutamylation of Glu6 residue of p6 and promoted IFN-I production to block the immune evasion of HIV-1. These findings not only reveal a previously unknown mechanism through which an HIV-1 protein mediate immune evasion, but also provide a new therapeutic drug candidate to treat HIV-1 infection.

2021-11-25 | GSE189384 | GEO

ARF1 prevents aberrant type I IFN induction by regulating STING activation and recycling

Project description:Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Afterwards, signal termination is achieved through autophagic degradation of STING, or STING recycling by retrograde COPI-mediated transport. Here we identify the GTPase ARF1 as a negative regulator of cGAS-STING signaling. Heterozygous ARF1 missense mutations cause a novel type I interferonopathy associated with enhanced IFN stimulated gene production. Expression of patient-derived, GTPase-defective, ARF1 in cell lines and primary cells results in increased cGAS-STING dependent type I IFN signalling. Mechanistically, mutated ARF1 both induces activation of cGAS by aberrant mitochondrial DNA, and promotes accumulation of active STING at the Golgi/ERGIC due to defective COPI retrograde transport. Our data establish ARF1 as a key factor in cGAS-STING homeostasis, which is required to maintain mitochondrial integrity and promote STING recycling.

2022-06-23 | MSV000089711 | MassIVE

Interferon Signaling After TBI in Aged Mice

Project description:Type I Interferons (IFN-I) contribute to the neuropathology of traumatic brain injury (TBI) and age-related neurodegenerative disease, where Cyclic GMP-AMP Synthase (cGAS) and the Stimulator of Interferon Genes (STING) pathway are implicated as key inducers of IFN-I responses. This study evaluated cGAS/STING activation, IFN-I signaling and neuroinflammation in the cortex and hippocampus of young and aged C57Bl/6 male mice, 24 hrs after controlled cortical impact injury. TBI increased expression of transcripts related to IFN-I signaling and activation of cGAS in the injured cortex of aged mice compared to younger mice. These observations were confirmed by RT-PCR, western blotting and phosphorylation/activation of STAT1, a downstream IFN-I effector molecule

2021-08-20 | GSE180811 | GEO

β-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion

Project description:β-arrestin 2 as an activator of cGAS-STING signaling and target of viral immune evasion

| PRJNA670348 | ENA

The noncanonical cGAS-STING-PERK pathway enables a selective translation program and underlies organ fibrosis

Project description:Innate DNA sensing via the cGAS-STING pathway surveys both microbial invasion and cellular damage, constituting a ubiquitous mechanism for host defense and tissue homeostasis. However, very little is known about the signaling mechanism(s) and physiological impacts downstream of cGAS-STING signaling and independent of the classical TBK1-IRF3-IFN cascade. Here, we identified an unrecognized STING-PERK-eIF2α signaling axis that was specific and controlled cap-dependent translation, a fundamental cellular process. STING, upon activation by 2'3'-cyclic GMP-AMP (cGAMP), robustly bound and directly activated the endoplasmic reticulum (ER)-located kinase PERK, and this process was upstream of IRF3 activation and independent of the unfolded protein response (UPR) and TBK1/IKKε. Innate DNA sensing suppressed global translation programs but selectively ensured the activation of some pathways by PERK-mediated eIF2α phosphorylation and the rapid regulation of protein synthesis, enabling translational modulation of immune responses. Notably, the STING-PERK-eIF2α axis is an evolutionarily primitive component of STING-TBKI-IRF3-IFN signaling and is physiologically critical in pulmonary and renal fibrosis as well as in the regulation of cellular senescence. Therefore, these findings establish the first noncanonical pathway of the cGAS-STING mechanism and demonstrate the physiological importance of this STING-triggered selective translation, which we propose as a promising therapeutic target for fibrotic diseases.

2024-01-18 | GSE165123 | GEO

The noncanonical cGAS-STING-PERK pathway enables a selective translation program and underlies organ fibrosis [STING2]

2022-03-07 | GSE165910 | GEO

Neddylation modification on cGAS of human and mouse

Project description:The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) has emerged as a fundamental component fueling the anti-pathogen immunity. Because of its pivotal role in initiating innate immune response, the activity of cGAS must be tightly fine-tuned to maintain immune homeostasis in antiviral response. Here, we reported that neddylation modification was indispensable for appropriate cGAS-STING signaling activation. Blocking neddylation pathway using neddylation inhibitor MLN4924 substantially impaired the induction of type I interferon and proinflammatory cytokines, which was selectively dependent on Nedd8 E2 enzyme Ube2m. We further found that deficiency of the Nedd8 E3 ligase Rnf111 greatly attenuated DNA-triggered cGAS activation while not affecting cGAMP induced activation of STING, demonstrating that Rnf111 was the Nedd8 E3 ligase of cGAS. We further identified Lys231 and Lys421 as the key neddylation sites in human cGAS. Mechanistically, Rnf111 interacted with and polyneddylated cGAS, which in turn promoted its dimerization and enhanced the DNA-binding ability, leading to proper cGAS-STING pathway activation. In the same line, the Ube2m or Rnf111 deficiency mice exhibited severe defects in innate immune response and were susceptible to HSV-1 infection. Collectively, our study uncovered a vital role of the Ube2m-Rnf111 neddylation axis in promoting the activity of the cGAS-STING pathway and highlighted the importance of neddylation modification in antiviral defense.

2021-02-22 | PXD024088 | Pride

Interleukin-1β induces mitochondrial DAMP production to activate STING-dependent innate immune programs

Project description:Here we report that exogenous IL-1β induces TBK1-mediated interferon regulatory factor 3 (IRF3) activation and autophagic flux in human myeloid and epithelial cells. IL-1β-induced innate immune activation is dependent upon the DNA sensing pathway adaptor, stimulator of interferon genes (STING), through the recognition of mitochondrial DNA by cyclic GMP-AMP synthase (cGAS). Thus, IL-1β potentiates pathogen-induced interferon production and signal transducer and activator of transcription (STAT) signaling to amplify innate immune responses.

2018-09-21 | GSE120269 | GEO

The cytosolic DNA sensor cGAS recognizes Neutrophil Extracellular Traps

Project description:Neutrophil Extracellular Traps (NETs) are structures consisting of chromatin and antimicrobial molecules that are released by neutrophils during a form of regulated cell death called NETosis. NETs trap invading pathogens, promote coagulation and activate myeloid cells to produce Type I interferons (type I IFN), proinflammatory cytokines that regulate the immune system. The mechanism of NET recognition by myeloid cells is not yet clearly identified. Here we show that macrophages and other myeloid cells phagocytose NETs. Once in phagosomes, NETs translocate to the cytosol, where they activate the DNA sensor cyclic GMP-AMP synthase (cGAS) and induce type I IFN expression. cGAS recognizes the DNA backbone of NETs. Interestingly, the NET associated serine protease Neutrophil Elastase (NE) mediates the activation of the pathway. We confirmed that NETs activate cGAS in vivo. Thus, our findings identify cGAS as a major sensor of NETs, mediating the immune activation during infection and in auto-immune diseases.

2021-02-18 | PXD015579 | Pride

Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience II

Project description:Here we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of cGAS in tauopathy mice diminished microglial IFN-I response, preserved synapse integrity and plasticity, and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation enhanced, while activation of IFN-I downregulated, neuronal MEF2C expression network linked with cognitive resilience in AD.

2023-04-26 | GSE226381 | GEO

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