Cell Reports (Nov 2024)
ADA2 is a lysosomal deoxyadenosine deaminase acting on DNA involved in regulating TLR9-mediated immune sensing of DNA
- Ole Kristian Greiner-Tollersrud,
- Máté Krausz,
- Vincent Boehler,
- Aikaterini Polyzou,
- Maximilian Seidl,
- Ambra Spahiu,
- Zeinab Abdullah,
- Katarzyna Andryka-Cegielski,
- Felix Immunuel Dominick,
- Katrin Huebscher,
- Andreas Goschin,
- Cristian R. Smulski,
- Eirini Trompouki,
- Regina Link,
- Hilmar Ebersbach,
- Honnappa Srinivas,
- Martine Marchant,
- Georgios Sogkas,
- Dieter Staab,
- Cathrine Vågbø,
- Danilo Guerini,
- Sebastian Baasch,
- Eicke Latz,
- Gunther Hartmann,
- Philippe Henneke,
- Roger Geiger,
- Xiao P. Peng,
- Bodo Grimbacher,
- Eva Bartok,
- Ingrun Alseth,
- Max Warncke,
- Michele Proietti
Affiliations
- Ole Kristian Greiner-Tollersrud
- Institute of Medical Biology, University of Tromsø, Tromsø, Norway
- Máté Krausz
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany
- Vincent Boehler
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
- Aikaterini Polyzou
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; IRCAN Institute for Research on Cancer and Aging, INSERM Unité 1081, CNRS UMR 7284, Université Côte d'Azur, Nice, France
- Maximilian Seidl
- Institute of Pathology, University Hospital of Düsseldorf, Düsseldorf, Germany
- Ambra Spahiu
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany
- Zeinab Abdullah
- Institute of Experimental Immunology, Universitätsklinikum Bonn, Bonn, Germany
- Katarzyna Andryka-Cegielski
- Institute of Experimental Hematology and Transfusion Medicine Bonn, Bonn, Germany
- Felix Immunuel Dominick
- Institute of Experimental Hematology and Transfusion Medicine Bonn, Bonn, Germany
- Katrin Huebscher
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany; Institut für Forstentomologie und Waldschutz, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany
- Andreas Goschin
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany
- Cristian R. Smulski
- Medical Physics Department, Centro Atómico Bariloche, Comisión Nacional de Energía Atómica (CNEA), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), San Carlos de Bariloche, Río Negro, Argentina
- Eirini Trompouki
- Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany; IRCAN Institute for Research on Cancer and Aging, INSERM Unité 1081, CNRS UMR 7284, Université Côte d'Azur, Nice, France
- Regina Link
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
- Hilmar Ebersbach
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
- Honnappa Srinivas
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
- Martine Marchant
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
- Georgios Sogkas
- Department of Rheumatology and Clinical Immunology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; RESIST - Cluster of Excellence 2155, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany
- Dieter Staab
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
- Cathrine Vågbø
- Proteomics and Modomics Experimental Core (PROMEC), Norwegian University of Science and Technology and the Central Norway Regional Health Authority, Trondheim, Norway
- Danilo Guerini
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
- Sebastian Baasch
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany; Institute for Infection Prevention and Control, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Freiburg Institute for Advanced Studies (FRIAS), University of Freiburg, Freiburg, Germany
- Eicke Latz
- Institute of Innate Immunity, Universitätsklinikum Bonn, Bonn, Germany
- Gunther Hartmann
- Institute of Experimental Hematology and Transfusion Medicine Bonn, Bonn, Germany
- Philippe Henneke
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany; Institute for Infection Prevention and Control, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Roger Geiger
- Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland; Institute of Oncology Research, Università della Svizzera italiana, Bellinzona, Switzerland
- Xiao P. Peng
- Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Bodo Grimbacher
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany; RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany
- Eva Bartok
- Institute of Experimental Hematology and Transfusion Medicine Bonn, Bonn, Germany
- Ingrun Alseth
- Department of Microbiology, Oslo University Hospital, Oslo, Norway
- Max Warncke
- Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland
- Michele Proietti
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany; Department of Rheumatology and Clinical Immunology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; RESIST - Cluster of Excellence 2155, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany; Corresponding author
- Journal volume & issue
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Vol. 43,
no. 11
p. 114899
Abstract
Summary: Although adenosine deaminase 2 (ADA2) is considered an extracellular ADA, evidence questions the physiological relevance of this activity. Our study reveals that ADA2 localizes within the lysosomes, where it is targeted through modifications of its glycan structures. We show that ADA2 interacts with DNA molecules, altering their sequences by converting deoxyadenosine (dA) to deoxyinosine (dI). We characterize its DNA substrate preferences and provide data suggesting that DNA, rather than free adenosine, is its natural substrate. Finally, we demonstrate that dA-to-dI editing of DNA molecules and ADA2 regulate lysosomal immune sensing of nucleic acids (NAs) by modulating Toll-like receptor 9 (TLR9) activation. Our results describe a mechanism involved in the complex interplay between NA metabolism and immune response, possibly impacting ADA2 deficiency (DADA2) and other diseases involving this pathway, including autoimmune diseases, cancer, or infectious diseases.
