Nucleotide-Induced Membrane-Proximal Proteolysis Controls the Substrate Specificity of T Cell Ecto-ADP-Ribosyltransferase ARTC2.2
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Nucleotide-Induced Membrane-Proximal Proteolysis Controls the Substrate Specificity of T Cell Ecto-ADP-Ribosyltransferase ARTC2.2. / Menzel, Stephan; Rissiek, Björn; Bannas, Peter; Jakoby, Thomas; Miksiewicz, Maria; Schwarz, Nicole; Nissen, Marion; Haag, Friedrich; Tholey, Andreas; Nolte, Friedrich.
In: J IMMUNOL, Vol. 195, No. 5, 01.09.2015, p. 2057-2066.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Nucleotide-Induced Membrane-Proximal Proteolysis Controls the Substrate Specificity of T Cell Ecto-ADP-Ribosyltransferase ARTC2.2
AU - Menzel, Stephan
AU - Rissiek, Björn
AU - Bannas, Peter
AU - Jakoby, Thomas
AU - Miksiewicz, Maria
AU - Schwarz, Nicole
AU - Nissen, Marion
AU - Haag, Friedrich
AU - Tholey, Andreas
AU - Nolte, Friedrich
N1 - Copyright © 2015 by The American Association of Immunologists, Inc.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - ARTC2.2 is a toxin-related, GPI-anchored ADP-ribosyltransferase expressed by murine T cells. In response to NAD(+) released from damaged cells during inflammation, ARTC2.2 ADP-ribosylates and thereby gates the P2X7 ion channel. This induces ectodomain shedding of metalloprotease-sensitive cell surface proteins. In this study, we show that ARTC2.2 itself is a target for P2X7-triggered ectodomain shedding. We identify the metalloprotease cleavage site 3 aa upstream of the predicted GPI anchor attachment site of ARTC2.2. Intravenous injection of NAD(+) increased the level of enzymatically active ARTC2.2 in serum, indicating that this mechanism is operative also under inflammatory conditions in vivo. Radio-ADP-ribosylation assays reveal that shedding refocuses the target specificity of ARTC2.2 from membrane proteins to secretory proteins. Our results uncover nucleotide-induced membrane-proximal proteolysis as a regulatory mechanism to control the substrate specificity of ARTC2.2.
AB - ARTC2.2 is a toxin-related, GPI-anchored ADP-ribosyltransferase expressed by murine T cells. In response to NAD(+) released from damaged cells during inflammation, ARTC2.2 ADP-ribosylates and thereby gates the P2X7 ion channel. This induces ectodomain shedding of metalloprotease-sensitive cell surface proteins. In this study, we show that ARTC2.2 itself is a target for P2X7-triggered ectodomain shedding. We identify the metalloprotease cleavage site 3 aa upstream of the predicted GPI anchor attachment site of ARTC2.2. Intravenous injection of NAD(+) increased the level of enzymatically active ARTC2.2 in serum, indicating that this mechanism is operative also under inflammatory conditions in vivo. Radio-ADP-ribosylation assays reveal that shedding refocuses the target specificity of ARTC2.2 from membrane proteins to secretory proteins. Our results uncover nucleotide-induced membrane-proximal proteolysis as a regulatory mechanism to control the substrate specificity of ARTC2.2.
U2 - 10.4049/jimmunol.1401677
DO - 10.4049/jimmunol.1401677
M3 - SCORING: Journal article
C2 - 26209623
VL - 195
SP - 2057
EP - 2066
JO - J IMMUNOL
JF - J IMMUNOL
SN - 0022-1767
IS - 5
ER -