RNA-sensing TLRs are strategically positioned in the endolysosome to detect incoming nonself RNA. RNase T2 plays a critical role in processing long, structured RNA into short oligoribonucleotides that engage TLR7 or TLR8. In addition to its positive regulatory role, RNase T2 also restricts RNA recognition through unknown mechanisms, as patients deficient in RNase T2 suffer from neuroinflammation. Consistent with this, mice lacking RNase T2 exhibit interferon-dependent neuroinflammation, impaired hematopoiesis, and splenomegaly. However, the mechanism by which RNase T2 deficiency unleashes inflammation in vivo remains unknown. Here, we report that the inflammatory phenotype found in Rnaset2−/− mice is completely reversed in the absence of TLR13, suggesting aberrant accumulation of an RNA ligand for this receptor. Interestingly, this TLR13-driven inflammatory phenotype is also fully present in germ-free mice, suggesting a role for RNase T2 in limiting erroneous TLR13 activation by an as yet unidentified endogenous ligand. These results establish TLR13 as a potential self-sensor that is kept in check by RNase T2.
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Brief Definitive Report|
January 24 2025
RNase T2 restricts TLR13-mediated autoinflammation in vivo
Carlos Gomez-Diaz
,
Carlos Gomez-Diaz
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Writing - original draft, Writing - review & editing)
1Gene Center and Department of Biochemistry,
Ludwig-Maximilians-Universität München
, Munich, Germany
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Wilhelm Greulich
,
Wilhelm Greulich
(Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation)
1Gene Center and Department of Biochemistry,
Ludwig-Maximilians-Universität München
, Munich, Germany
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Benedikt Wefers
,
Benedikt Wefers
(Methodology, Resources)
2
Institute of Developmental Genetics, Helmholtz Zentrum München
, Neuherberg, Germany
3
TUM School of Life Sciences, Technische Universität München
, Freising-Weihenstephan, Germany
4
Deutsches Zentrum für Neurodegenerative Erkrankungen Site Munich
, Munich, Germany
5
Munich Cluster for Systems Neurology (SyNergy)
, Munich, Germany
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Meiyue Wang
,
Meiyue Wang
(Data curation, Investigation, Methodology, Writing - review & editing)
1Gene Center and Department of Biochemistry,
Ludwig-Maximilians-Universität München
, Munich, Germany
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Silvia Bolsega
,
Silvia Bolsega
(Investigation, Methodology, Resources, Writing - review & editing)
6Institute for Laboratory Animal Science,
Hannover Medical School
, Hannover, Germany
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Maike Effern
,
Maike Effern
(Formal analysis, Investigation, Methodology)
7
Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn
, Bonn, Germany
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Daniel P. Varga
,
Daniel P. Varga
(Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing - original draft)
8
Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-Universität München
, Munich, Germany
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Zhe Han
,
Zhe Han
(Investigation)
9
Institute for Immunology, Heidelberg University Hospital
, Heidelberg, Germany
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Minyi Chen
,
Minyi Chen
(Investigation)
9
Institute for Immunology, Heidelberg University Hospital
, Heidelberg, Germany
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Marleen Bérouti
,
Marleen Bérouti
(Investigation)
1Gene Center and Department of Biochemistry,
Ludwig-Maximilians-Universität München
, Munich, Germany
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Natascia Leonardi
,
Natascia Leonardi
(Formal analysis, Investigation)
1Gene Center and Department of Biochemistry,
Ludwig-Maximilians-Universität München
, Munich, Germany
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Ulrike Schillinger
,
Ulrike Schillinger
(Resources)
1Gene Center and Department of Biochemistry,
Ludwig-Maximilians-Universität München
, Munich, Germany
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Bernhard Holzmann
,
Bernhard Holzmann
(Resources, Writing - review & editing)
10Department of Surgery,
TUM School of Medicine and Health, Technical University of Munich
, Munich, Germany
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Arthur Liesz
,
Arthur Liesz
(Funding acquisition, Supervision, Validation)
5
Munich Cluster for Systems Neurology (SyNergy)
, Munich, Germany
8
Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-Universität München
, Munich, Germany
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Axel Roers
,
Axel Roers
(Investigation, Supervision, Visualization)
9
Institute for Immunology, Heidelberg University Hospital
, Heidelberg, Germany
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Michael Hölzel
,
Michael Hölzel
(Project administration, Resources, Supervision, Writing - review & editing)
7
Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn
, Bonn, Germany
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Marijana Basic
,
Marijana Basic
(Funding acquisition, Investigation, Methodology, Project administration, Resources, Writing - review & editing)
6Institute for Laboratory Animal Science,
Hannover Medical School
, Hannover, Germany
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Wolfgang Wurst
,
Wolfgang Wurst
(Conceptualization, Funding acquisition, Methodology, Resources, Writing - original draft)
2
Institute of Developmental Genetics, Helmholtz Zentrum München
, Neuherberg, Germany
3
TUM School of Life Sciences, Technische Universität München
, Freising-Weihenstephan, Germany
4
Deutsches Zentrum für Neurodegenerative Erkrankungen Site Munich
, Munich, Germany
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Veit Hornung
(Conceptualization, Data curation, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing)
1Gene Center and Department of Biochemistry,
Ludwig-Maximilians-Universität München
, Munich, Germany
Correspondence to Veit Hornung: [email protected]
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Carlos Gomez-Diaz
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Validation, Writing - original draft, Writing - review & editing
1Gene Center and Department of Biochemistry,
Ludwig-Maximilians-Universität München
, Munich, Germany
Wilhelm Greulich
Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation
1Gene Center and Department of Biochemistry,
Ludwig-Maximilians-Universität München
, Munich, Germany
Benedikt Wefers
Methodology, Resources
2
Institute of Developmental Genetics, Helmholtz Zentrum München
, Neuherberg, Germany
3
TUM School of Life Sciences, Technische Universität München
, Freising-Weihenstephan, Germany
4
Deutsches Zentrum für Neurodegenerative Erkrankungen Site Munich
, Munich, Germany
5
Munich Cluster for Systems Neurology (SyNergy)
, Munich, Germany
Meiyue Wang
Data curation, Investigation, Methodology, Writing - review & editing
1Gene Center and Department of Biochemistry,
Ludwig-Maximilians-Universität München
, Munich, Germany
Silvia Bolsega
Investigation, Methodology, Resources, Writing - review & editing
6Institute for Laboratory Animal Science,
Hannover Medical School
, Hannover, Germany
Maike Effern
Formal analysis, Investigation, Methodology
7
Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn
, Bonn, Germany
Daniel P. Varga
Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing - original draft
8
Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-Universität München
, Munich, Germany
Zhe Han
Investigation
9
Institute for Immunology, Heidelberg University Hospital
, Heidelberg, Germany
Minyi Chen
Investigation
9
Institute for Immunology, Heidelberg University Hospital
, Heidelberg, Germany
Marleen Bérouti
Investigation
1Gene Center and Department of Biochemistry,
Ludwig-Maximilians-Universität München
, Munich, Germany
Natascia Leonardi
Formal analysis, Investigation
1Gene Center and Department of Biochemistry,
Ludwig-Maximilians-Universität München
, Munich, Germany
Ulrike Schillinger
Resources
1Gene Center and Department of Biochemistry,
Ludwig-Maximilians-Universität München
, Munich, Germany
Bernhard Holzmann
Resources, Writing - review & editing
10Department of Surgery,
TUM School of Medicine and Health, Technical University of Munich
, Munich, Germany
Arthur Liesz
Funding acquisition, Supervision, Validation
5
Munich Cluster for Systems Neurology (SyNergy)
, Munich, Germany
8
Institute for Stroke and Dementia Research, University Hospital, Ludwig-Maximilians-Universität München
, Munich, Germany
Axel Roers
Investigation, Supervision, Visualization
9
Institute for Immunology, Heidelberg University Hospital
, Heidelberg, Germany
Michael Hölzel
Project administration, Resources, Supervision, Writing - review & editing
7
Institute of Experimental Oncology, Medical Faculty, University Hospital Bonn
, Bonn, Germany
Marijana Basic
Funding acquisition, Investigation, Methodology, Project administration, Resources, Writing - review & editing
6Institute for Laboratory Animal Science,
Hannover Medical School
, Hannover, Germany
Wolfgang Wurst
Conceptualization, Funding acquisition, Methodology, Resources, Writing - original draft
2
Institute of Developmental Genetics, Helmholtz Zentrum München
, Neuherberg, Germany
3
TUM School of Life Sciences, Technische Universität München
, Freising-Weihenstephan, Germany
4
Deutsches Zentrum für Neurodegenerative Erkrankungen Site Munich
, Munich, Germany
Veit Hornung
Conceptualization, Data curation, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Validation, Visualization, Writing - original draft, Writing - review & editing
1Gene Center and Department of Biochemistry,
Ludwig-Maximilians-Universität München
, Munich, Germany
Correspondence to Veit Hornung: [email protected]
Disclosures: W. Wurst reported a patent (W02014/131833) issued: “Generation of mouse models using CRISPR/Cas9 in zygotes is patented (WO2014/131833).” No other disclosures were reported.
Received:
August 11 2024
Revision Received:
November 18 2024
Accepted:
December 20 2024
Online ISSN: 1540-9538
Print ISSN: 0022-1007
Funding
Funder(s):
European Research Council
- Award Id(s): ERC-2020-ADG–101018672 ENGINES
Funder(s):
Deutsche Forschungsgemeinschaft
- Award Id(s): CRC 237/A27,CRC 237/B17,CRC 1371
© 2025 Gomez-Diaz et al.
2025
Gomez-Diaz et al.
This article is distributed under the terms as described at https://rupress.org/pages/terms102024/.
J Exp Med (2025) 222 (3): e20241424.
Article history
Received:
August 11 2024
Revision Received:
November 18 2024
Accepted:
December 20 2024
Citation
Carlos Gomez-Diaz, Wilhelm Greulich, Benedikt Wefers, Meiyue Wang, Silvia Bolsega, Maike Effern, Daniel P. Varga, Zhe Han, Minyi Chen, Marleen Bérouti, Natascia Leonardi, Ulrike Schillinger, Bernhard Holzmann, Arthur Liesz, Axel Roers, Michael Hölzel, Marijana Basic, Wolfgang Wurst, Veit Hornung; RNase T2 restricts TLR13-mediated autoinflammation in vivo. J Exp Med 3 March 2025; 222 (3): e20241424. doi: https://doi.org/10.1084/jem.20241424
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