Absence of RNase H2 triggers generation of immunogenic micronuclei removed by autophagy
Open accessAbstract
Hypomorphic mutations in the DNA repair enzyme RNase H2 cause the neuroinflammatory autoimmune disorder Aicardi-Goutières syndrome (AGS). Endogenous nucleic acids are believed to accumulate in patient cells and instigate pathogenic type I interferon expression. However, the underlying nucleic acid species amassing in the absence of RNase H2 has not been established yet. Here, we report that murine RNase H2 knockout cells accumulated cytosolic DNA aggregates virtually indistinguishable from micronuclei. RNase H2-dependent micronuclei were surrounded by nuclear lamina and most of them contained damaged DNA. Importantly, they induced expression of interferon-stimulated genes (ISGs) and co-localized with the nucleic acid sensor cGAS. Moreover, micronuclei associated with RNase H2 deficiency were cleared by autophagy. Consequently, induction of autophagy by pharmacological mTOR inhibition resulted in a significant reduction of cytosolic DNA and the accompanied interferon signature. Autophagy induction might therefore represent a viable therapeutic option for RNase H2-dependent disease. Endogenous retroelements have previously been proposed as a source of self-nucleic acids triggering inappropriate activation of the immune system in AGS. We used human RNase H2-knockout cells generated by CRISPR/Cas9 to investigate the impact of RNase H2 on retroelement propagation. Surprisingly, replication of LINE-1 and Alu elements was blunted in cells lacking RNase H2, establishing RNase H2 as essential host factor for the mobilisation of endogenous retrotransposons.
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cGAS activation caused by rupture of the MN nuclear envelope is thought to be the main trigger of an interferon-based inflammatory response.
“Similarly, cGAS activation due to rupture of the MN nuclear envelope is thought to be the major trigger of an interferon-based inflammatory response (Bartsch et al., 2017; Gekara, 2017; Harding et al., 2017; Mackenzie et al., 2017).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Bartsch et al., 2017
Loss of nuclear membrane integrity in senescent cells and laminopathies, such as HGPS, parallels loss of membrane integrity in micronuclei.
“For example, the loss of nuclear membrane integrity in senescent cells (Shimi et al., 2011) and laminopathies, such as HGPS, parallels loss of membrane integrity in MN (Bartsch et al., 2017; Gekara, 2017; Harding et al., 2017; Mackenzie et al., 2017).”
From Cytoplasmic DNA: sources, sensing, and role in aging and disease (2021) · cites this paper as Bartsch et al., 2017
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“Two independent studies showed that RNaseH2-null cells, which have been previously shown to express higher levels of IFN-induced genes, probably through a STING-mediated pathway [11,69], have increased numbers of micronuclei in their cytoplasm [12,14].”
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“Micronuclei colocalize with cGAS, which induces a type I IFN response (Bartsch et al. 2017, Gluck et al. 2017, Harding et al. 2017, Mackenzie et al. 2017, Yang et al. 2017).”
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BackgroundTranslation stress and collided ribosomes are co-activators of cGAS
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“Moreover, even sterile means to increase micronuclei formation, such as genetic alterations in RNase H2, associated with autoimmunity in humans, favoring formation of chromosome bridges, promoted a cGAS/STING-driven inflammatory response [165,166].”
CGAS is a micronucleophagy receptor for the clearance of micronuclei
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“In addition, micronuclei associated with RNase H2 deficiency have been linked to autophagy in mice, as pharmacological mammalian target of rapamacyn (mTOR) inhibition resulted in a significant reduction of cytosolic DNA and the accompanying IFN signature (Bartsch et al., 2017).”
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“Furthermore, our findings are consistent with a recent report that also found RNase H2 to be required for retrotransposition (Bartsch et al , 2017).”
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“Indeed, STING-dependent autophagy degrades Mycobacterium tuberculosis (17), micronuclei or damaged DNA (63, 64), and ruptured mitochondria (65), thereby counter-regulating activation of STING by cGAS.”
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“…which then recruit their own nuclear envelope to generate micronuclei. cGAS is recruited to micronuclei upon rupture of their nuclear envelope (Bartsch et The EMBO Journal Carina C de Oliveira Mann & Karl-Peter Hopfner cytosolic compartment and in recruitment and activation of the cytosolic…”
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“The principal DNA sensor is cGAS (cyclic AMPGMP Synthase) which binds to the signalling scaffold STING (Stimulator of Interferon Genes) which transmits a signal directly to type I interferon genes and signals via the noncanonical pathway to Nuclear Factor kB (NF-kB) which powerfully activates cell-autonomous innate im…”
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“…cyclic GMP-AMP (cGAMP) from ATP and GTP. cGAMP binds to the adaptor Stimulator of Interferon Genes (STING), activating a STAT3-dependent signaling pathway, leading to the transcription of pro-inflammatory type I Interferon (Bartsch et al. 2017; Harding et al. 2017; Mackenzie et al. 2017).”
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“Although it has been most recently reported that CRISPR/Cas9mediated knockout of RNASEH2A leads to a substantially reduced retrotransposition (34), the role of RNASEH2 in L1 metabolism is thus far not fully proven.”
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“Recent reports demonstrate that defects in RNase H2 result in micronuclei that provide cytoplasmic DNA to stimulate the innate immune response via the cGAS-Sting pathway (Bartsch et al., 2017; Mackenzie et al., 2017).”
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TREX1 – Apex predator of cytosolic DNA metabolism
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“…( TREX1 , RNASEH2 genes and SAMHD1 ) leads to type I IFN induction via cGAS (Ablasser et al , 2014; Gao et al , 2015; Gray et al , 2015; Mackenzie et al , 2016; Maelfait et al , 2016; Pokatayev et al , 2016; Bartsch et al , 2017; Mackenzie et al , 2017; Coquel et al , 2018; Xiao et al , 2019).”
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“Although micronuclei are a consequence of chromosome missegregation [62], they can be reabsorbed during subsequent cell divisions or destroyed by autophagy [63,64].”
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“These cytoplasmic membrane-bound DNA co-localized with the innate immune sensor cGAS, providing direct evidence for DNA damage mediated activation of cGAS-STING pathway in RNASEH2 mutations (3).”
BackgroundThe triggers of the cGAS-STING pathway and the connection with inflammatory and autoimmune diseases
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“The excess of micronuclei in AGS cells also stimulates autophagy, which in turn targets micronuclei for lysosomal degradation, therefore preventing further stimulation of the innate immune response [110].”
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“Inhibition of autophagy, as a consequence, aggravated the IFN response [50].”
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“More speci fi cally, it appears autophagy can clear micronuclei (Bartsch et al., 2017) and damaged mitochondria (Lindqvist et al., 2018) before they can release dsDNA into the cytosol.”
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“Recent findings have provided mechanistic insights into how the accumulation of chromatin fragments in the form of micronuclei and the subsequent rupture of the nuclear envelope initiate the cGAS-STING-mediated cytosolic DNA sensing pathway (Bartsch et al., 2017; Dou et al., 2017; Gluck et al., 2017; Harding et al., 2…”
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“In addition, mutations of ribonucle-ase (RNase) H2, an endonuclease specifically targeting RNA strands of hybrid duplexes, can cause the human Aicardi-Goutières syndrome and an increase in micronuclei triggering a persistent inflammatory activation, likely at the basis of the syndrome ( 35 – 37 ).”
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- Authors
- Bartsch, K., Knittler, K., Borowski, C., Rudnik, S., Damme, M., Aden, K., Spehlmann, M. E., Frey, N., Saftig, P., Chalaris, A., & Rabe, B.
- Affiliations
- Christian-Albrechts-Universität zu Kiel (DE)
- University Hospital Schleswig-Holstein (DE)
- Corresponding author
- Rabe, Björn
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2017-07-17
- Volume
- 26
- Issue
- 20
- Pages
- 3960-3972
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2735349030
- Cited by
- 196
- References
- 52
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 18 · 2023: 23 · 2022: 20 · 2021: 27 · 2020: 25 · 2019: 28 · 2018: 31 · 2017: 2
- FWCI
- 10.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (RA 2404/1-1)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- RNase H2, Aicardi-Goutières syndrome, autophagy, micronuclei, cytosolic DNA, type I interferon, cGAS, interferon-stimulated genes, endogenous retrotransposons, LINE-1, Alu elements, mTOR inhibition, DNA repair, neuroinflammation
- MeSH terms
- Animals, Autophagy, DNA, DNA Damage, DNA Replication, Mutation, Nervous System Malformations, Ribonuclease H, Mice, Knockout, Autoimmune Diseases of the Nervous System, Micronucleus, Germline, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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