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

Cell reports

Authors: 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

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.

Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

PMID: 39441717

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