ADP-Ribosylation Regulates the Signaling Function of IFN-γ
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ADP-Ribosylation Regulates the Signaling Function of IFN-γ. / Menzel, Stephan; Koudelka, Tomas; Rissiek, Björn; Haag, Friedrich; Meyer-Schwesinger, Catherine; Tholey, Andreas; Koch-Nolte, Friedrich.
In: FRONT IMMUNOL, Vol. 12, 2021, p. 642545.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - ADP-Ribosylation Regulates the Signaling Function of IFN-γ
AU - Menzel, Stephan
AU - Koudelka, Tomas
AU - Rissiek, Björn
AU - Haag, Friedrich
AU - Meyer-Schwesinger, Catherine
AU - Tholey, Andreas
AU - Koch-Nolte, Friedrich
N1 - Copyright © 2021 Menzel, Koudelka, Rissiek, Haag, Meyer-Schwesinger, Tholey and Koch-Nolte.
PY - 2021
Y1 - 2021
N2 - Murine T cells express the GPI-anchored ADP-ribosyltransferase 2.2 (ARTC2.2) on the cell surface. In response to T cell activation or extracellular NAD+ or ATP-mediated gating of the P2X7 ion channel ARTC2.2 is shed from the cell surface as a soluble enzyme. Shedding alters the target specificity of ARTC2.2 from cell surface proteins to secreted proteins. Here we demonstrate that shed ARTC2.2 potently ADP-ribosylates IFN-γ in addition to other cytokines. Using mass spectrometry, we identify arginine 128 as the target site of ADP-ribosylation. This residue has been implicated to play a key role in binding of IFN-γ to the interferon receptor 1 (IFNR1). Indeed, binding of IFN-γ to IFNR1 blocks ADP-ribosylation of IFN-γ. Moreover, ADP-ribosylation of IFN-γ inhibits the capacity of IFN-γ to induce STAT1 phosphorylation in macrophages and upregulation of the proteasomal subunit ß5i and the proteasomal activator PA28-α in podocytes. Our results show that ADP-ribosylation inhibits the signaling functions of IFN-γ and point to a new regulatory mechanism for controlling signaling by IFN-γ.
AB - Murine T cells express the GPI-anchored ADP-ribosyltransferase 2.2 (ARTC2.2) on the cell surface. In response to T cell activation or extracellular NAD+ or ATP-mediated gating of the P2X7 ion channel ARTC2.2 is shed from the cell surface as a soluble enzyme. Shedding alters the target specificity of ARTC2.2 from cell surface proteins to secreted proteins. Here we demonstrate that shed ARTC2.2 potently ADP-ribosylates IFN-γ in addition to other cytokines. Using mass spectrometry, we identify arginine 128 as the target site of ADP-ribosylation. This residue has been implicated to play a key role in binding of IFN-γ to the interferon receptor 1 (IFNR1). Indeed, binding of IFN-γ to IFNR1 blocks ADP-ribosylation of IFN-γ. Moreover, ADP-ribosylation of IFN-γ inhibits the capacity of IFN-γ to induce STAT1 phosphorylation in macrophages and upregulation of the proteasomal subunit ß5i and the proteasomal activator PA28-α in podocytes. Our results show that ADP-ribosylation inhibits the signaling functions of IFN-γ and point to a new regulatory mechanism for controlling signaling by IFN-γ.
U2 - 10.3389/fimmu.2021.642545
DO - 10.3389/fimmu.2021.642545
M3 - SCORING: Journal article
C2 - 33763084
VL - 12
SP - 642545
JO - FRONT IMMUNOL
JF - FRONT IMMUNOL
SN - 1664-3224
ER -
