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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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“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
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“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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Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › 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
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