A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are major sheddases of T cell immunoglobulin and mucin domain 3 (Tim-3)
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A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are major sheddases of T cell immunoglobulin and mucin domain 3 (Tim-3). / Möller-Hackbarth, Katja; Dewitz, Christin; Schweigert, Olga; Trad, Ahmad; Garbers, Christoph; Rose-John, Stefan; Scheller, Jürgen.
in: J BIOL CHEM, Jahrgang 288, Nr. 48, 29.11.2013, S. 34529-34544.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are major sheddases of T cell immunoglobulin and mucin domain 3 (Tim-3)
AU - Möller-Hackbarth, Katja
AU - Dewitz, Christin
AU - Schweigert, Olga
AU - Trad, Ahmad
AU - Garbers, Christoph
AU - Rose-John, Stefan
AU - Scheller, Jürgen
PY - 2013/11/29
Y1 - 2013/11/29
N2 - T cell immunoglobulin and mucin domain 3 (Tim-3) dampens the response of CD4(+) and CD8(+) effector T cells via induction of cell death and/or T cell exhaustion and enhances the ability of macrophages to clear pathogens via binding to galectin 9. Here we provide evidence that human Tim-3 is a target of A disintegrin and metalloprotease (ADAM)-mediated ectodomain shedding resulting in a soluble form of Tim-3. We identified ADAM10 and ADAM17 as major sheddases of Tim-3 as shown by ADAM-specific inhibitors and the ADAM10 pro-domain in HEK293 cells and ADAM10/ADAM17-deficient murine embryonic fibroblasts. PMA-induced shedding of Tim-3 was abrogated by deletion of amino acids Glu(181)-Asp(190) of the stalk region and Tim-3 lacking the intracellular domain was not efficiently cleaved after PMA stimulation. Surprisingly, a single lysine residue within the intracellular domain rescues shedding of Tim-3. Shedding of endogenous Tim-3 was found in primary human CD14(+) monocytes after PMA and ionomycin stimulation. Importantly, the recently described down-regulation of Tim-3 from Toll-like receptor-activated CD14(+) monocytes was caused by ADAM10- and ADAM17-mediated shedding. Inhibition of Tim-3 shedding from lipopolysaccharide-induced monocytes did not influence lipopolysaccharide-induced TNFα and IL-6 but increases IL-12 expression. In summary, we describe Tim-3 as novel target for ADAM-mediated ectodomain shedding and suggest a role of Tim-3 shedding in TLR-mediated immune responses of CD14(+) monocytes.
AB - T cell immunoglobulin and mucin domain 3 (Tim-3) dampens the response of CD4(+) and CD8(+) effector T cells via induction of cell death and/or T cell exhaustion and enhances the ability of macrophages to clear pathogens via binding to galectin 9. Here we provide evidence that human Tim-3 is a target of A disintegrin and metalloprotease (ADAM)-mediated ectodomain shedding resulting in a soluble form of Tim-3. We identified ADAM10 and ADAM17 as major sheddases of Tim-3 as shown by ADAM-specific inhibitors and the ADAM10 pro-domain in HEK293 cells and ADAM10/ADAM17-deficient murine embryonic fibroblasts. PMA-induced shedding of Tim-3 was abrogated by deletion of amino acids Glu(181)-Asp(190) of the stalk region and Tim-3 lacking the intracellular domain was not efficiently cleaved after PMA stimulation. Surprisingly, a single lysine residue within the intracellular domain rescues shedding of Tim-3. Shedding of endogenous Tim-3 was found in primary human CD14(+) monocytes after PMA and ionomycin stimulation. Importantly, the recently described down-regulation of Tim-3 from Toll-like receptor-activated CD14(+) monocytes was caused by ADAM10- and ADAM17-mediated shedding. Inhibition of Tim-3 shedding from lipopolysaccharide-induced monocytes did not influence lipopolysaccharide-induced TNFα and IL-6 but increases IL-12 expression. In summary, we describe Tim-3 as novel target for ADAM-mediated ectodomain shedding and suggest a role of Tim-3 shedding in TLR-mediated immune responses of CD14(+) monocytes.
KW - ADAM Proteins/genetics
KW - ADAM17 Protein
KW - Animals
KW - CD4-Positive T-Lymphocytes/metabolism
KW - CD8-Positive T-Lymphocytes/metabolism
KW - Disintegrins/metabolism
KW - Down-Regulation
KW - Fibroblasts/metabolism
KW - Galectins/metabolism
KW - Gene Expression Regulation
KW - HEK293 Cells
KW - Hepatitis A Virus Cellular Receptor 2
KW - Humans
KW - Membrane Proteins/genetics
KW - Mice
KW - Monocytes/metabolism
KW - Signal Transduction
KW - Tumor Necrosis Factor-alpha/genetics
U2 - 10.1074/jbc.M113.488478
DO - 10.1074/jbc.M113.488478
M3 - SCORING: Journal article
C2 - 24121505
VL - 288
SP - 34529
EP - 34544
JO - J BIOL CHEM
JF - J BIOL CHEM
SN - 0021-9258
IS - 48
ER -