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

doi:10.1016/j.celrep.2024.114899

ADA2 is a lysosomal deoxyadenosine deaminase acting on DNA involved in regulating TLR9-mediated immune sensing of DNA

Cell Rep. 2024 Oct 22;43(11):114899. doi: 10.1016/j.celrep.2024.114899. Online ahead of print.

Authors

Ole Kristian Greiner-Tollersrud¹, Máté Krausz², Vincent Boehler³, Aikaterini Polyzou⁴, Maximilian Seidl⁵, Ambra Spahiu², Zeinab Abdullah⁶, Katarzyna Andryka-Cegielski⁷, Felix Immunuel Dominick⁷, Katrin Huebscher⁸, Andreas Goschin², Cristian R Smulski⁹, Eirini Trompouki⁴, Regina Link³, Hilmar Ebersbach³, Honnappa Srinivas³, Martine Marchant³, Georgios Sogkas¹⁰, Dieter Staab³, Cathrine Vågbø¹¹, Danilo Guerini³, Sebastian Baasch¹², Eicke Latz¹³, Gunther Hartmann⁷, Philippe Henneke¹⁴, Roger Geiger¹⁵, Xiao P Peng¹⁶, Bodo Grimbacher¹⁷, Eva Bartok⁷, Ingrun Alseth¹⁸, Max Warncke³, Michele Proietti¹⁹

Affiliations

¹ Institute of Medical Biology, University of Tromsø, Tromsø, Norway.
² Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, Freiburg im Breisgau, Germany.
³ Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland.
⁴ 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.
⁵ Institute of Pathology, University Hospital of Düsseldorf, Düsseldorf, Germany.
⁶ Institute of Experimental Immunology, Universitätsklinikum Bonn, Bonn, Germany.
⁷ Institute of Experimental Hematology and Transfusion Medicine Bonn, Bonn, Germany.
⁸ 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.
⁹ 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.
¹⁰ 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.
¹¹ Proteomics and Modomics Experimental Core (PROMEC), Norwegian University of Science and Technology and the Central Norway Regional Health Authority, Trondheim, Norway.
¹² 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.
¹³ Institute of Innate Immunity, Universitätsklinikum Bonn, Bonn, Germany.
¹⁴ 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.
¹⁵ Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland; Institute of Oncology Research, Università della Svizzera italiana, Bellinzona, Switzerland.
¹⁶ Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹⁷ 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.
¹⁸ Department of Microbiology, Oslo University Hospital, Oslo, Norway.
¹⁹ 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. Electronic address: [email protected].

PMID: 39441717
DOI: 10.1016/j.celrep.2024.114899

Abstract

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.

Keywords: ADA2; CP: Immunology; DADA2; DNA editing; TLR9; Toll-like receptors; innate immunity; inosine; nucleic acid immunity; nucleic-acid sensing; type I interferon.