Cutting Edge: cGAS Is Required for Lethal Autoimmune Disease in the Trex1-Deficient Mouse Model of Aicardi–Goutières Syndrome

Gray, Elizabeth; Treuting, Piper M.; Woodward, Joshua J.; Stetson, Daniel B.

doi:10.4049/jimmunol.1500969

Cited by 324 publications

(282 citation statements)

References 27 publications

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“…These results reveal cGAS as an important molecular link between DNA damage, SASP gene expression, and senescence. This conclusion is consistent with the previous reports that cGAS is activated by dsDNA independently of the DNA sequence and that cGAS activation by endogenous DNA causes autoimmune diseases in mice lacking the DNase Trex1 or DNaseII (22,43,44). Surprisingly, we found that Sting gt/gt MEFs, which have been shown to lack the STING protein and are completely defective in the cytosolic DNA signaling pathway, were more resistant to spontaneous immortalization than cGas −/− MEFs (Fig.…”

Section: Discussionsupporting

confidence: 94%

cGAS is essential for cellular senescence

Yang

Wang

Ren

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

767

733

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Cellular senescence is a natural barrier to tumorigenesis and it contributes to the antitumor effects of several therapies, including radiation and chemotherapeutic drugs. Senescence also plays an important role in aging, fibrosis, and tissue repair. The DNA damage response is a key event leading to senescence, which is characterized by the senescence-associated secretory phenotype (SASP) that includes expression of inflammatory cytokines. Here we show that cGMP-AMP (cGAMP) synthase (cGAS), a cytosolic DNA sensor that activates innate immunity, is essential for senescence. Deletion of cGAS accelerated the spontaneous immortalization of mouse embryonic fibroblasts. cGAS deletion also abrogated SASP induced by spontaneous immortalization or DNA damaging agents, including radiation and etoposide. cGAS is localized in the cytoplasm of nondividing cells but enters the nucleus and associates with chromatin DNA during mitosis in proliferating cells. DNA damage leads to accumulation of damaged DNA in cytoplasmic foci that contain cGAS. In human lung adenocarcinoma patients, low expression of cGAS is correlated with poor survival. These results indicate that cGAS mediates cellular senescence and retards immortalization. This is distinct from, and complementary to, the role of cGAS in activating antitumor immunity.ellular senescence is a state of irreversible cell cycle arrest triggered by various types of cellular and environmental stress, such as telomere shortening, oncogene activation, and DNA damage (1, 2). Senescence appears to be an antiproliferation process that limits the growth of damaged cells and acts as a potent barrier to tumorigenesis (3, 4). Senescence is characterized by several unique features, including enlarged and flattened cell morphology (5), increased senescence-associated β-galactosidase (SA-β-Gal) activity (6, 7), and in some cell types, a widespread change in chromatin modification, known as senescence-associated heterochromatin foci (SAHF) (7). At the molecular level, the p53-p21 WAF1 and pRb-p16 INK4a tumor suppressor pathways have been reported to be key mechanisms that control the execution and maintenance of senescence (8,9). In addition to these cellular features, senescent cells also undergo massive changes in the expression of genes that are thought to affect the tissue microenvironment (5). Senescent cells secrete a variety of soluble factors including inflammatory cytokines, growth factors, and proteases; such senescence-associated secretory phenotype (SASP) is a hallmark of senescence (10-12).Components of SASP not only serve as a marker of senescence, but also participate in the senescence process (13). Interleukin 6 (IL6) and IL8, two key components of SASP, reinforce the senescence growth arrest in neighboring cells (14,15). Additionally, these cytokines and other secreted factors attract immune cells, leading to the elimination of senescent cells (16). Given these important functions, SASP is regulated at both transcriptional and epigenetic levels, such as by nuclear factor κB (NF...

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Section: Discussionsupporting

confidence: 94%

cGAS is essential for cellular senescence

Yang

Wang

Ren

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

767

733

View full text Add to dashboard Cite

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“…IFNAR ), and cGAS -/-mice were provided by the MG and Dan Stetson (University of Washington). IFNAR -/-and cGAS -/-mice were bred as heterozygotes for experiments with littermate controls after genotyping as previously described (93,94). All mice used for experimental purposes were male and aged 6-10 weeks.…”

Section: Methodsmentioning

confidence: 99%

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

Hahn¹,

Butler²,

Lindner³

et al. 2018

JCI Insight

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“…Trex1 −/− mice succumb to systemic inflammation early in age, largely due to immune activation by self-DNA through the cGAS-STING-TBK1-IRF3 pathway (6,7). Upon activation by DNA, cGAS produces cyclic GMP-AMP (cGAMP) dinucleotide that activates STING on the ER.…”

Section: Significancementioning

confidence: 99%

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism

Hašan

Gonugunta

Dobbs

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Three-prime repair exonuclease 1 knockout (Trex1 −/− ) mice suffer from systemic inflammation caused largely by chronic activation of the cyclic GMP-AMP synthase-stimulator of interferon genes-TANKbinding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) signaling pathway. We showed previously that Trex1-deficient cells have reduced mammalian target of rapamycin complex 1 (mTORC1) activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1 −/− mice and cells that revealed both cellular and systemic metabolic defects, including reduced mitochondrial respiration and increased glycolysis, energy expenditure, and fat metabolism. We also genetically separated the inflammatory and metabolic phenotypes by showing that Sting deficiency rescued both inflammatory and metabolic phenotypes, whereas Irf3 deficiency only rescued inflammation on the Trex1 −/− background, and many metabolic defects persist in Trex1 −/− Irf3 −/− cells and mice. We also showed that Leptin deficiency (ob/ob) increased lipogenesis and prolonged survival of Trex1 −/− mice without dampening inflammation. Mechanistically, we identified TBK1 as a key regulator of mTORC1 activity in Trex1 −/− cells. Together, our data demonstrate that chronic innate immune activation of TBK1 suppresses mTORC1 activity, leading to dysregulated cellular metabolism.M ammals have evolved complex and integrated systems of immunity and metabolism to maintain and defend internal and environmental threats. Increasing numbers of immune regulators have been found to play critical roles in metabolism. Studies from recent years have established an integrated view on the shared architecture between adaptive immunity and metabolism, including how they correspond to stimulus in disease settings. However, cell-intrinsic innate immune regulation of metabolic pathways remains poorly understood. This is in part due to the fact that overwhelming systemic inflammation in chronic diseases often masks direct underlying molecular causes.We have previously characterized an autoimmune/autoinflammatory disease mouse model, three-prime repair exonuclease 1 knockout (Trex1 −/− ) (1). TREX1, also known as DNase III, is an exonuclease that localizes to the endoplasmic reticulum (ER) to prevent aberrant accumulation of self-DNA or glycans that would trigger immune activation (2, 3). Mutations of the TREX1 gene have been associated with several autoinflammatory and autoimmune diseases, including Aicardi-Goutières syndrome and systemic lupus erythematosus (SLE) (4). Trex1 −/− mice suffer from systemic inflammation caused largely by chronic activation of the cytosolic DNA sensing pathway through the cyclic GMP-AMP synthase-stimulator of interferon genes-TANK-binding kinase-interferon regulatory factor 3 (cGAS-STING-TBK1-IRF3) cascade (5-7). We showed previously that TREX1 also regulates lysosomal biogenesis through the mTORC1-TFEB pathway and that Trex1 −/− mouse embryonic fibroblasts (MEFs) exhibit drastically reduced mTORC1 activity compare...

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Cutting Edge: cGAS Is Required for Lethal Autoimmune Disease in the Trex1-Deficient Mouse Model of Aicardi–Goutières Syndrome

Cited by 324 publications

References 27 publications

cGAS is essential for cellular senescence

cGAS is essential for cellular senescence

cGAS-mediated control of blood-stage malaria promotes Plasmodium-specific germinal center responses

Chronic innate immune activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism

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