Ecto-ADP-ribosyltransferase ARTC2.1 functionally modulates FcγR1 and FcγR2B on murine microglia
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Ecto-ADP-ribosyltransferase ARTC2.1 functionally modulates FcγR1 and FcγR2B on murine microglia. / Rissiek, Björn; Menzel, Stephan; Leutert, Mario; Cordes, Maike; Behr, Sarah; Jank, Larissa; Ludewig, Peter; Gelderblom, Mathias; Rissiek, Anne; Adriouch, Sahil; Haag, Friedrich; Hottiger, Michael O; Koch-Nolte, Friedrich; Magnus, Tim.
in: SCI REP-UK, Jahrgang 7, Nr. 1, 28.11.2017, S. 16477.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Ecto-ADP-ribosyltransferase ARTC2.1 functionally modulates FcγR1 and FcγR2B on murine microglia
AU - Rissiek, Björn
AU - Menzel, Stephan
AU - Leutert, Mario
AU - Cordes, Maike
AU - Behr, Sarah
AU - Jank, Larissa
AU - Ludewig, Peter
AU - Gelderblom, Mathias
AU - Rissiek, Anne
AU - Adriouch, Sahil
AU - Haag, Friedrich
AU - Hottiger, Michael O
AU - Koch-Nolte, Friedrich
AU - Magnus, Tim
PY - 2017/11/28
Y1 - 2017/11/28
N2 - 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 32P-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.
AB - 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 32P-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.
KW - Journal Article
U2 - 10.1038/s41598-017-16613-w
DO - 10.1038/s41598-017-16613-w
M3 - SCORING: Journal article
C2 - 29184112
VL - 7
SP - 16477
JO - SCI REP-UK
JF - SCI REP-UK
SN - 2045-2322
IS - 1
ER -