Deficiency for SAMHD1 activates MDA5 in a cGAS/STING-dependent manner

Author:

Schumann Tina1ORCID,Ramon Santiago Costas1ORCID,Schubert Nadja1ORCID,Mayo Mohamad Aref2ORCID,Hega Melanie2ORCID,Maser Katharina Isabell2ORCID,Ada Servi-Remzi1ORCID,Sydow Lukas1ORCID,Hajikazemi Mona3ORCID,Badstübner Markus1ORCID,Müller Patrick2ORCID,Ge Yan14ORCID,Shakeri Farhad56ORCID,Buness Andreas56ORCID,Rupf Benjamin7ORCID,Lienenklaus Stefan8ORCID,Utess Barbara1,Muhandes Lina12ORCID,Haase Michael9ORCID,Rupp Luise1ORCID,Schmitz Marc11011ORCID,Gramberg Thomas12ORCID,Manel Nicolas13ORCID,Hartmann Gunther2ORCID,Zillinger Thomas2ORCID,Kato Hiroki14ORCID,Bauer Stefan7ORCID,Gerbaulet Alexander1ORCID,Paeschke Katrin3ORCID,Roers Axel14ORCID,Behrendt Rayk12ORCID

Affiliation:

1. Institute for Immunology, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany 1

2. Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn, Germany 2

3. Clinic of Internal Medicine III, Oncology, Hematology, Rheumatology and Clinical Immunology, University Hospital Bonn, Bonn, Germany 3

4. Institute for Immunology, University Hospital Heidelberg, Heidelberg, Germany 4

5. Institute for Medical Biometry, Informatics and Epidemiology, Medical Faculty, University of Bonn, Bonn, Germany 5

6. Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Bonn, Germany 6

7. Institute for Immunology, Philipps-University Marburg, Marburg, Germany 7

8. Institute of Laboratory Animal Science, Hannover Medical School, Hannover, Germany 8

9. Department of Pediatric Surgery, University Hospital Dresden, Dresden, Germany 9

10. National Center for Tumor Diseases, Partner Site Dresden, Dresden, Germany 10

11. German Cancer Consortium, Partner Site Dresden, and German Cancer Research Center, Heidelberg, Germany 11

12. Institute of Clinical and Molecular Virology, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany 12

13. Institut national de la santé et de la recherche médicale U932, Institut Curie, Paris Sciences et Lettres Research University, Paris, France 13

14. Institute of Cardiovascular Immunology, Medical Faculty, University Hospital Bonn, Bonn, Germany 14

Abstract

Defects in nucleic acid metabolizing enzymes can lead to spontaneous but selective activation of either cGAS/STING or RIG-like receptor (RLR) signaling, causing type I interferon–driven inflammatory diseases. In these pathophysiological conditions, activation of the DNA sensor cGAS and IFN production are linked to spontaneous DNA damage. Physiological, or tonic, IFN signaling on the other hand is essential to functionally prime nucleic acid sensing pathways. Here, we show that low-level chronic DNA damage in mice lacking the Aicardi-Goutières syndrome gene SAMHD1 reduced tumor-free survival when crossed to a p53-deficient, but not to a DNA mismatch repair-deficient background. Increased DNA damage did not result in higher levels of type I interferon. Instead, we found that the chronic interferon response in SAMHD1-deficient mice was driven by the MDA5/MAVS pathway but required functional priming through the cGAS/STING pathway. Our work positions cGAS/STING upstream of tonic IFN signaling in Samhd1-deficient mice and highlights an important role of the pathway in physiological and pathophysiological innate immune priming.

Funder

Deutsche Forschungsgemeinschaft

Aicardi-Goutières Syndrome Advocacy Association

Fritz-Thyssen-Stiftung

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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