Intercellular cGAMP transmission induces innate immune activation and tissue inflammation in Trex1 deficiency
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ABSTRACT:
PROVIDER: PRJNA735518 | ENA |
REPOSITORIES: ENA
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Project description:Intercellular transmission of the second messenger 2′,3′‐cGAMP, synthesized by the viral DNA sensor cGAMP synthase (cGAS), is a potent mode of bystander activation during host defense. However, whether this mechanism also contributes to cGAS-dependent autoimmunity remains unknown. Here, using a murine bone marrow transplantation strategy, we demonstrate that, in Trex1-/--associated autoimmunity, cGAMP shuttling from radioresistant to immune cells induces NF-κB activation, interferon regulatory protein 3 (IRF3) phosphorylation and subsequent interferon signaling. cGAMP travel prevented myeloid cell and lymphocyte death, promoting their accumulation in secondary lymphoid tissue. Nonetheless, it did not stimulate B cell differentiation into autoantibody-producing plasmablasts or aberrant T cell priming in the steady state. Although cGAMP-mediated bystander activation did not induce spontaneous organ disease, it did trigger interface dermatitis after UV light exposure, similar to cutaneous lupus erythematosus. These findings reveal that, in Trex1-deficiency, intercellular cGAMP transfer propagates cGAS signaling and, under conducive conditions, causes tissue inflammation.
2021-07-09 | GSE176225 | GEO
Project description: Not available
| S-EPMC8326191 | biostudies-literature
Project description:bacterial amyloidosis, prion-like, RepA-WH1, intercellular transmission,proteotoxic cross-aggregation
2020-05-26 | PXD018245 | Pride
Project description:Intracellular microbes have evolved efficient strategies for transitioning from one cell to another in a process termed intercellular transmission. Here we show that host cell transmission of the obligate intracellular parasite Toxoplasma gondii is closely tied to specific cell cycle distributions, with egress and reinvasion occurring most proficiently by parasites in the G1 phase. We also reveal that Toxoplasma undergoes marked changes in mRNA expression when transitioning from the extracellular environment to its intracellular niche. These mRNA level changes reflect a modal switch from expression of proteins involved in invasion, motility and signal transduction in extracellular parasites to expression of metabolic and DNA replication proteins in intracellular parasites. Host cell binding and signalling associated with the discharge of parasite secretory proteins was not sufficient to induce this switch in gene expression, suggesting that the regulatory mechanisms responsible are tied to the establishment of the intracellular environment. The genes whose expression increased after parasite invasion belong to a progressive cascade known to underlie the parasite division cycle indicating that the unique relationship between the G1 phase and invasion effectively synchronizes short-term population growth. This work provides new insight into how this highly successful parasite competently transits from cell to cell. Three sample types were harvested: extracellular, intracellular 0hr, intracellular 2hr. 2 replicates each. Expression for >80% of the regulated genes exhibits a steady downregulation during invasion.
2010-12-27 | E-GEOD-20480 | biostudies-arrayexpress
Project description:Intracellular microbes have evolved efficient strategies for transitioning from one cell to another in a process termed intercellular transmission. Here we show that host cell transmission of the obligate intracellular parasite Toxoplasma gondii is closely tied to specific cell cycle distributions, with egress and reinvasion occurring most proficiently by parasites in the G1 phase. We also reveal that Toxoplasma undergoes marked changes in mRNA expression when transitioning from the extracellular environment to its intracellular niche. These mRNA level changes reflect a modal switch from expression of proteins involved in invasion, motility and signal transduction in extracellular parasites to expression of metabolic and DNA replication proteins in intracellular parasites. Host cell binding and signalling associated with the discharge of parasite secretory proteins was not sufficient to induce this switch in gene expression, suggesting that the regulatory mechanisms responsible are tied to the establishment of the intracellular environment. The genes whose expression increased after parasite invasion belong to a progressive cascade known to underlie the parasite division cycle indicating that the unique relationship between the G1 phase and invasion effectively synchronizes short-term population growth. This work provides new insight into how this highly successful parasite competently transits from cell to cell.
2010-12-27 | GSE20480 | GEO
Project description:Given that TREX1-deficient tumor cells showed a growth delay in immunocompetent but not immunodeficient hosts, we characterize the consequences of CT26 tumor-intrinsic TREX1 loss on the host immune system by performing single-cell RNA sequencing on intra-tumoral immune cells sorted from control and TREX1 KO CT26 tumors.
2024-03-12 | E-MTAB-13823 | biostudies-arrayexpress
Project description:ENPP1 expression correlates with poor prognosis in many cancers, and we previously discovered that ENPP1 is the dominant hydrolase of extracellular cGAMP: a cancer-cell-produced immunotransmitter that activates the anticancer STING pathway. However, ENPP1 has other catalytic activities and the molecular and cellular mechanisms contributing to its tumorigenic effects remain unclear. Here, using single cell RNA-seq (scRNA-seq), we show that ENPP1 overexpression drives primary tumor growth and metastasis by synergistically dampening extracellular cGAMP-STING mediated antitumoral immunity and activating immunosuppressive extracellular adenosine (eADO) signaling. In addition to cancer cells, stromal and immune cells in the tumor microenvironment (TME) also express ENPP1 which functions as a gate keeper to block cGAMP sensing in these cells. Enpp1 knockout in both cancer cells and normal tissues slowed primary tumor growth and prevented metastasis in an extracellular cGAMP- and STING-dependent manner. Lastly, an ENPP1 knock-in mutation that selectively abolishes ENPP1’s cGAMP hydrolysis activity phenocopied total ENPP1 knockout, demonstrating that restoration of paracrine cGAMP-STING signaling is the dominant anti-cancer mechanism of ENPP1 inhibition. In summary, selectively blocking ENPP1’s cGAMP hydrolysis activity is a promising therapeutic approach for treating cancer.
2023-08-07 | GSE233659 | GEO
Project description:DNA sensing is a fundamental process in the immune system, including host defence against viruses. The DNA sensor cGAS synthesises 2’3’ cyclic GMP-AMP (cGAMP), a second messenger that activates STING, which subsequently induces innate immunity. cGAMP not only activates STING in the cell where it is produced but also transfers to other cells. Transporters, channels and pores including SLC19A1, the SLC46A family, P2X7, ABCC1 and volume-regulated anion channels (VRACs) release cGAMP into the extracellular space and/or import cGAMP into cells. Emerging evidence suggests these proteins are important in antiviral immunity. Here, we investigated whether viruses antagonise cGAMP transporters, channels and pores. We report that infection with multiple human viruses depleted cGAMP conduits from cells. This included herpes simplex virus 1 (HSV-1) that targeted the VRAC subunits LRRC8A and LRRC8C, as well as SLC46A2 and P2X7, for degradation. The HSV-1 protein UL56 was required and sufficient for these effects that were mediated at least partially by proteasomal turnover. UL56 thereby inhibited the cGAMP uptake via VRAC, SLC46A2 and P2X7. Taken together, we show that HSV-1 actively antagonises cGAMP transfer across the plasma membrane and propose this limits innate immunity by reducing cell-to-cell communication via the immunotransmitter cGAMP.
2024-04-15 | PXD043229 | Pride
Project description:Astrocyte diversity is greatly influenced by local environmental modulation. In this study, we analyzed the impact of ciliary deficient astrocytes on astrocytes’ intercellular communications and neuronal transcriptomes in the brain. Our analysis revealed a broad disturbance of astrocyte intercellular connectomes and profound changes in neuronal transcriptomic profiles induced by ciliary deficiency in astrocytes.
2024-01-24 | GSE253642 | GEO