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RNAseq of mouse RAW264.7 macrophages with CRISPR deletion of SGK1, SGK3, or SGK1/3 or treated with SGKi Sanofi-14h with or without DMXAA stimulation.

ABSTRACT: The STING signaling pathway is essential for the innate immune response to DNA viruses and bacteria and is important in tumor immunity. STING binding to cGAMP or to synthetic agonists leads to the activation of the kinase TBK1 which phosphorylates the transcription factor IRF3 which promotes expression of type 1 interferons such as IFNb to block viral activity. Aberrant type 1 IFN expression is associated with human diseases including autoimmunity, HIV, and cancer. Here we identify N-[4-(1H-pyrazolo[3,4-b] pyrazin-6-yl)-phenyl]-sulfonamide (Sanofi-14h), a compound with preference for inhibition of the AGC family kinase SGK3, as an inhibitor of IFNb gene expression in response to STING stimulation of macrophages. Sanofi-14h abrogated SGK activity and also impaired activation of the critical TBK1/IRF3 pathway downstream of STING activation, notably blocking the ligand-induced interaction of STING with TBK1. Deletion of SGK1 and SGK3 in macrophages suppressed activation of IFNb transcription but did not block TBK1/IRF3 activation downstream of STING. Gene and protein expression analysis revealed that deletion of SGK1/3 in a macrophage cell line decreases basal expression of critical transcription factors required for the innate immune response, such as IRF7 and STAT1. Additional studies reveal that other AGC kinase inhibitors block TBK1 and IRF3 activation suggesting common action on a critical regulatory node in the STING pathway. Thus, studies with Sanofi-14h have revealed both SGK-dependent and SGK-independent effects in the STING pathway and suggest a mechanism to alter type 1 IFN transcription through small molecule therapy

ORGANISM(S): Mus musculus

PROVIDER: GSE243816 | GEO | 2023/09/26

REPOSITORIES: GEO

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Cyclic-Di-Nucleotides Trigger ULK1 (ATG1) Phosphorylation of STING to Prevent Sustained Innate Immune Signaling

Project description:Activation of the STING (Stimulator of Interferon Genes) pathway by microbial or self-DNA, as well as cyclic di nucleotides (CDN), results in the induction of numerous genes that suppress pathogen replication and facilitate adaptive immunity. However, sustained gene transcription is rigidly prevented to avoid lethal STING-dependent pro-inflammatory disease by mechanisms that remain unknown. We demonstrate here that after autophagy-dependent STING delivery of TBK1 (TANK-binding kinase 1) to endosomal/lysosomal compartments and activation of transcription factors IRF3 (interferon regulatory factors 3) and NF-κB (nuclear factor kappa beta), that STING is subsequently phosphorylated by serine/threonine UNC-51-like kinase (ULK1/ATG1) and IRF3 function is suppressed. ULK1 activation occurred following disassociation from its repressor adenine monophosphate activated protein kinase (AMPK), and was elicited by CDN’S generated by the cGAMP synthase, cGAS. Thus, while CDN’s may initially facilitate STING function, they subsequently trigger negative-feedback control of STING activity, thus preventing the persistent transcription of innate immune genes. Total RNA obtained from primary STING deficient mouse embryonic fibroblast reconstituted with mSTING (W), S365A variant (A), or S365D variant (D). These cells were transfected with dsDNA (ISD) for 3 hours.

2013-10-10 | E-GEOD-51199 | biostudies-arrayexpress

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

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.

2022-03-07 | GSE165910 | GEO

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

2024-01-18 | GSE165123 | GEO

Cyclic-Di-Nucleotides Trigger ULK1 (ATG1) Phosphorylation of STING to Prevent Sustained Innate Immune Signaling

2013-10-10 | GSE51199 | GEO

Characterization of SGK3-PROTAC1, a highly specific SGK3 kinase PROTAC degrader

Project description:SGK3 is a PX domain containing protein kinase activated at endosomes downstream of Class 1 and 3 PI3K family members by growth factors and oncogenic mutations. SGK3 plays a key role in mediating resistance of breast cancer to Class 1 PI3K or Akt inhibitors, by substituting for loss of Akt and restoring proliferative pathways such as mTORC1 signaling. Here we describe the development of SGK3-PROTAC1, a Proteolysis Targeting Chimera (PROTAC) compound formed by the fusion of the 308-R SGK3 inhibitor with the VH032 VHL binding ligand via a 13-atom linker. In HEK293 cells, 0.3 µM SGK3-PROTAC1 induced 50% degradation of endogenous SGK3 within 2 hours, with maximal 85% degradation observed within 8 hours, accompanied by a loss of phosphorylation of NDRG1, an SGK3 substrate. SGK3-PROTAC1 did not degrade closely related SGK1 and SGK2 isoforms and proteomic analysis in HEK293 cells revealed that SGK3 was the only cellular protein whose cellular levels was significantly reduced following treatment with SGK3-PROTAC1. Low doses of SGK3-PROTAC1 (0.1-0.3 µM) restored sensitivity of SGK3 dependent ZR-75-1 and CAMA-1 breast cancer cells to Akt (AZD5363) and PI3K (GDC0941) inhibitors, under conditions which an epimer analogue incapable of binding to the VHL E3 ligase had no impact. SGK3-PROTAC1 suppressed proliferation of ZR-75-1 and CAMA-1 cancer cell lines treated with a PI3K inhibitor (GDC0941) more effectively than could be achieved by a conventional SGK isoform inhibitor (14H). This work provides a further example of the benefit of the PROTAC approach in targeting protein kinase signaling pathways with greater efficacy and selectivity than can be achieved with conventional inhibitors. SGK3-PROTAC1 will be an important reagent to explore the roles of the SGK3 pathway.

2019-11-12 | PXD013779 | Pride

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

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

ScRNA-seq of Lineage-tracing Mice Identifies Smooth Muscle Cell Phenotypic Alterations in Aortic Aneurysms and Dissections

Project description:ScRNA-seq analysis revealed that aortic stress induced the transition of SMCs from a primary contractile phenotype to proliferative, extracellular matrix (ECM)-producing, inflammatory, and dying phenotypes. Lineage tracing showed the complete transformation of SMCs to fibroblasts and macrophages. ScATAC-seq analysis indicated that these phenotypic alterations were controlled by chromatin remodeling marked by the reduced chromatin accessibility of contractile genes and the induced chromatin accessibility of genes involved in ECM, inflammation, and cell death. IRF3, a pro-inflammatory transcription factor activated by cytosolic DNA, was identified as a key driver for the transition of aortic SMCs from a contractile phenotype to an inflammatory phenotype. In cultured SMCs, cytosolic DNA signaled through its sensor STING-TBK1 to activate IRF3, which bound and recruited EZH2 to contractile genes to induce repressive H3K27me3 modification and contractile gene suppression. In contrast, dsDNA-STING-IRF3 signaling induced inflammatory gene expression in SMCs. In Sting-/- mice, the aortic stress–induced transition of SMCs into an inflammatory phenotype was prevented, and SMC populations were preserved. Finally, profound SMC phenotypic alterations in diverse directions were detected in human ATAAD tissues.

2023-09-05 | GSE233257 | GEO

ScRNA-seq of Sting-KO Mice Identifies Smooth Muscle Cell Phenotypic Alterations in Aortic Aneurysms and Dissections

2023-09-05 | GSE233625 | GEO

hnRNPM, ELAVL1, and TBK1 form a type I interferon-inducing multiprotein complex downstream of cGAS and RIG-I

Project description:RIG-I like helicases (RLHs) and cGAS are crucial cytosolic sensors of viral RNA and DNA, respectively, and induce type I IFNs via TBK1/IKKε. hnRNPM was described to possess antimicrobial activities. Here, we show that hnRNPM promotes TBK1/IRF3 phosphorylation and type I IFN induction downstream of cGAS and RIG-I in THP-1 cells and primary human fibroblasts. Interactome analysis revealed that hnRNPM forms a multiprotein complex with ELAVL1, SON, TBK1, IKKε, IKKβ, and NF-κB p65. The purified hnRNPM complex enhanced TBK1 phosphorylation. Vice versa, TBK1 directly phosphorylated ELAVL1. hnRNPM, ELAVL1, and TBK1 predominantly interacted in the cytosol. Of note, patients with mutations in SON suffer from recurrent infections, further underlining its biologic significance. To our knowledge, hnRNPM, ELAVL1, and SON represent the first non-redundant signaling components merging the cGAS-STING and RIG-I–MAVS pathways. Therefore, our findings may have implications for host defense and auto-inflammatory diseases.

2023-09-16 | GSE184273 | GEO

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