Loss of the DNA Damage Repair Kinase ATM Impairs Inflammasome-Dependent Anti-Bacterial Innate Immunity

Erttmann, Saskia F.; Härtlová, Anetta; Słoniecka, Marta; Raffi, Faizal A.M.; Hosseinzadeh, Ava; Edgren, Tomas; Rofougaran, Reza; Resch, Ulrike; Fällman, Maria; Ek, Torben; Gekara, Nelson O.

doi:10.1016/j.immuni.2017.11.014

Cited by 7 publications

(8 citation statements)

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“…This result highlights the presence of an alternative pathway for generating IL-1␤ that is independent of the NLRP3 inflammasome. This is a significant finding as this NLRP3-containing inflammasome complex is impaired in the absence of ATM (Erttmann et al, 2016), but is highly active in other neurodegenerative diseases, such as Alzheimer's disease (Akiyama et al, 2000).…”

Section: Discussionmentioning

confidence: 89%

Accumulation of Cytoplasmic DNA Due to ATM Deficiency Activates the Microglial Viral Response System with Neurotoxic Consequences

2019

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ATM (ataxia-telangiectasia mutated) is a PI3K-like kinase best known for its role in the DNA damage response (DDR), especially after double-strand breaks. Mutations in the ATM gene result in a condition known as ataxia-telangiectasia (A-T) that is characterized by cancer predisposition, radiosensitivity, neurodegeneration, sterility, and acquired immune deficiency. We show here that the innate immune system is not spared in AT. ATM-deficient microglia adopt an active phenotype that includes the overproduction of proinflammatory cytokines that are toxic to cultured neurons and likely contribute to AT neurodegeneration. Causatively, ATM dysfunction results in the accumulation of DNA in the cytoplasm of microglia as well as a variety of other cell types. In microglia, cytoplasmic DNA primes an antiviral response via the DNA sensor, STING (stimulator of interferon genes). The importance of this response pathway is supported by our finding that inhibition of STING blocks the overproduction of neurotoxic cytokines. Cytosolic DNA also activates the AIM2 (absent in melanoma 2) containing inflammasome and induces proteolytic processing of cytokine precursors such as pro-IL-1␤. Our study furthers our understanding of neurodegeneration in AT and highlights the role of cytosolic DNA in the innate immune response.

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Section: Discussionmentioning

confidence: 89%

Accumulation of Cytoplasmic DNA Due to ATM Deficiency Activates the Microglial Viral Response System with Neurotoxic Consequences

2019

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“…Here, we addressed the pro-longevity benefits of CQ-activated ATM, most likely attributable to improved DNA repair and glucose metabolism. Given that ATM also displays anti-inflammatory function ( Erttmann et al, 2017 ; Shoelson, 2006 ), we could not rule out an anti-inflammatory effect in lifespan extension observed in CQ-treated mice.…”

Section: Discussionmentioning

confidence: 97%

Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria

Qian

Liu

et al. 2018

eLife

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DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans, but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases.

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“…Emerging evidence indicates that these two systems are interdependent (Hartlova et al, 2015) and that defects in these two systems lie at the heart of many diseases such as infections, autoimmunity, cancer, and aging-associated disorders including neurodegeneration (Hartlova et al, 2015;Erttmann et al, 2016). The molecular factors involved in the cross-talk between the DDR and the innate immune system, as well as the underlying mechanisms, remain poorly defined.…”

Section: Introductionmentioning

confidence: 99%

Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death

et al. 2019

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DNA repair via homologous recombination (HR) is indispensable for genome integrity and cell survival but if unrestrained can result in undesired chromosomal rearrangements. The regulatory mechanisms of HR are not fully understood. Cyclic GMP‐AMP synthase (cGAS) is best known as a cytosolic innate immune sensor critical for the outcome of infections, inflammatory diseases, and cancer. Here, we report that cGAS is primarily a chromatin‐bound protein that inhibits DNA repair by HR, thereby accelerating genome destabilization, micronucleus generation, and cell death under conditions of genomic stress. This function is independent of the canonical STING‐dependent innate immune activation and is physiologically relevant for irradiation‐induced depletion of bone marrow cells in mice. Mechanistically, we demonstrate that inhibition of HR repair by cGAS is linked to its ability to self‐oligomerize, causing compaction of bound template dsDNA into a higher‐ordered state less amenable to strand invasion by RAD51‐coated ssDNA filaments. This previously unknown role of cGAS has implications for understanding its involvement in genome instability‐associated disorders including cancer.

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Loss of the DNA Damage Repair Kinase ATM Impairs Inflammasome-Dependent Anti-Bacterial Innate Immunity

Cited by 7 publications

References 0 publications

Accumulation of Cytoplasmic DNA Due to ATM Deficiency Activates the Microglial Viral Response System with Neurotoxic Consequences

Accumulation of Cytoplasmic DNA Due to ATM Deficiency Activates the Microglial Viral Response System with Neurotoxic Consequences

Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria

Chromatin‐bound cGAS is an inhibitor of DNA repair and hence accelerates genome destabilization and cell death

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