Ecto-ADP-ribosyltransferase ARTC2.1 functionally modulates FcγR1 and FcγR2B on murine microglia

Björn Rissiek , Stephan Menzel (1) , Mario Leutert , Maike Cordes , Sarah Behr , Larissa Jank , Peter Ludewig , Mathias Gelderblom , Anne Rissiek , Sahil Adriouch (2) , Friedrich Haag (3) , Michael O Hottiger , Friedrich Koch-Nolte (3) , Tim Magnus

1 FZJ - Forschungszentrum Jülich GmbH | Centre de recherche de Jülich | Jülich Research Centre
2 Physiopathologie et biothérapies des maladies inflammatoires et autoimmunes
3 Institute for Immunology

Mammalian ecto-ADP-ribosyltransferases (ecto-ARTs or also ARTCs) catalyze the ADP-ribosylation of cell surface proteins using extracellular nicotinamide adenine dinucleotide (NAD +) as substrate. By this post-translational protein modification, ecto-ARTs modulate the function of various target proteins. A functional role of ARTC2 has been demonstrated for peripheral immune cells such as T cells and macrophages. Yet, little is known about the role of ecto-ARTs in the central nervous system and on microglia. Here, we identified ARTC2.1 as the major ecto-ART expressed on murine microglia. ARTC2.1 expression was strongly upregulated on microglia upon co-stimulation with LPS and an ERK1/2 inhibitor or upon IFNβ stimulation. We identified several target proteins modified by ARTC2.1 on microglia with a recently developed mass spectrometry approach, including two receptors for immunoglobulin G (IgG), FcγR1 and FcγR2B. Both proteins were verified as targets of ARTC2.1 in vitro using a radiolabeling assay with 32 P-NAD + as substrate. Moreover, ADP-ribosylation of both targets strongly inhibited their capacity to bind IgG. In concordance, ARTC2.1 induction in WT microglia and subsequent cell surface ADP-ribosylation significantly reduced the phagocytosis of IgG-coated latex beads, which was unimpaired in NAD + /DTT treated microglia from ARTC2.1 −/− mice. Hence, induction of ARTC2.1 expression under inflammatory conditions, and subsequent ADP-ribosylation of cell surface target proteins could represent a hitherto unnoticed mechanism to regulate the immune response of murine microglia.

Domaines: Immunologie

Björn Rissiek, Stephan Menzel, Mario Leutert, Maike Cordes, Sarah Behr, et al.. Ecto-ADP-ribosyltransferase ARTC2.1 functionally modulates FcγR1 and FcγR2B on murine microglia. Scientific Reports, 2017, 7 (1), ⟨10.1038/s41598-017-16613-w⟩. ⟨hal-02375773⟩