Species specificity of ADAM10 and ADAM17 proteins in interleukin-6 (IL-6) trans-signaling and novel role of ADAM10 in inducible IL-6 receptor shedding.
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Species specificity of ADAM10 and ADAM17 proteins in interleukin-6 (IL-6) trans-signaling and novel role of ADAM10 in inducible IL-6 receptor shedding. / Garbers, Christoph; Jänner, Nathalie; Chalaris, Athena; Moss, Marcia L; Floss, Doreen M; Meyer, Dörte; Koch Nolte, Friedrich; Rose-John, Stefan; Scheller, Jürgen.
in: J BIOL CHEM, Jahrgang 286, Nr. 17, 17, 2011, S. 14804-14811.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Species specificity of ADAM10 and ADAM17 proteins in interleukin-6 (IL-6) trans-signaling and novel role of ADAM10 in inducible IL-6 receptor shedding.
AU - Garbers, Christoph
AU - Jänner, Nathalie
AU - Chalaris, Athena
AU - Moss, Marcia L
AU - Floss, Doreen M
AU - Meyer, Dörte
AU - Koch Nolte, Friedrich
AU - Rose-John, Stefan
AU - Scheller, Jürgen
PY - 2011
Y1 - 2011
N2 - Hypomorphic ADAM17(ex/ex) mice showed defects in mucosal regeneration due to inefficient enhanced GFR shedding. ADAM17 is the main sheddase of interleukin-6 receptor (IL-6R) to induce IL-6 trans-signaling. However, serum levels of soluble murine IL-6R were not reduced in ADAM17(ex/ex) mice, and murine ADAM17 was not the major sheddase of murine IL-6R. Shedding of murine IL-6R by murine ADAM17 was rescued in chimeric murine IL-6R proteins containing any extracellular domain but not the transmembrane and intracellular domain of human IL-6R. Apoptosis is a physiological stimulus of ADAM17-mediated shedding of human IL-6R. Even though apoptosis induced IL-6R shedding in mice, the responsible protease was identified as ADAM10. ADAM10 also was identified as protease responsible for ionomycin-induced shedding of murine and human IL-6R. However, in ADAM10-deficient murine embryonic fibroblasts, compensatory shedding of human IL-6R was mediated by ADAM17, but loss of ADAM10-mediated shedding of murine IL-6R was compensated by an as-yet-unidentified protease. Finally, we identified physiological purinergic P2X7 receptor stimulation as a novel inducer of murine and human IL-6R shedding solely mediated by ADAM10. In conclusion, we describe an unexpected species specificity of ADAM10 and ADAM17 and identified ADAM10 as novel inducible sheddase of IL-6R in mice and humans, which might have consequences for the interpretation of phenotypes from ADAM17- and ADAM10-deficient mice.
AB - Hypomorphic ADAM17(ex/ex) mice showed defects in mucosal regeneration due to inefficient enhanced GFR shedding. ADAM17 is the main sheddase of interleukin-6 receptor (IL-6R) to induce IL-6 trans-signaling. However, serum levels of soluble murine IL-6R were not reduced in ADAM17(ex/ex) mice, and murine ADAM17 was not the major sheddase of murine IL-6R. Shedding of murine IL-6R by murine ADAM17 was rescued in chimeric murine IL-6R proteins containing any extracellular domain but not the transmembrane and intracellular domain of human IL-6R. Apoptosis is a physiological stimulus of ADAM17-mediated shedding of human IL-6R. Even though apoptosis induced IL-6R shedding in mice, the responsible protease was identified as ADAM10. ADAM10 also was identified as protease responsible for ionomycin-induced shedding of murine and human IL-6R. However, in ADAM10-deficient murine embryonic fibroblasts, compensatory shedding of human IL-6R was mediated by ADAM17, but loss of ADAM10-mediated shedding of murine IL-6R was compensated by an as-yet-unidentified protease. Finally, we identified physiological purinergic P2X7 receptor stimulation as a novel inducer of murine and human IL-6R shedding solely mediated by ADAM10. In conclusion, we describe an unexpected species specificity of ADAM10 and ADAM17 and identified ADAM10 as novel inducible sheddase of IL-6R in mice and humans, which might have consequences for the interpretation of phenotypes from ADAM17- and ADAM10-deficient mice.
KW - Animals
KW - Humans
KW - Mice
KW - Species Specificity
KW - Signal Transduction
KW - ADAM Proteins/physiology
KW - Amyloid Precursor Protein Secretases/physiology
KW - Interleukin-6/metabolism
KW - Membrane Proteins/physiology
KW - Receptors, Interleukin-6/metabolism
KW - Animals
KW - Humans
KW - Mice
KW - Species Specificity
KW - Signal Transduction
KW - ADAM Proteins/physiology
KW - Amyloid Precursor Protein Secretases/physiology
KW - Interleukin-6/metabolism
KW - Membrane Proteins/physiology
KW - Receptors, Interleukin-6/metabolism
M3 - SCORING: Journal article
VL - 286
SP - 14804
EP - 14811
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 17
M1 - 17
ER -
