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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)

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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, Vol. 288, No. 48, 29.11.2013, p. 34529-34544.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Möller-Hackbarth, K, Dewitz, C, Schweigert, O, Trad, A, Garbers, C, Rose-John, S & Scheller, J 2013, 'A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are major sheddases of T cell immunoglobulin and mucin domain 3 (Tim-3)', J BIOL CHEM, vol. 288, no. 48, pp. 34529-34544. https://doi.org/10.1074/jbc.M113.488478

APA

Möller-Hackbarth, K., Dewitz, C., Schweigert, O., Trad, A., Garbers, C., Rose-John, S., & Scheller, J. (2013). A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are major sheddases of T cell immunoglobulin and mucin domain 3 (Tim-3). J BIOL CHEM, 288(48), 34529-34544. https://doi.org/10.1074/jbc.M113.488478

Vancouver

Möller-Hackbarth K, Dewitz C, Schweigert O, Trad A, Garbers C, Rose-John S et al. A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are major sheddases of T cell immunoglobulin and mucin domain 3 (Tim-3). J BIOL CHEM. 2013 Nov 29;288(48):34529-34544. https://doi.org/10.1074/jbc.M113.488478

Bibtex

@article{304e5ed66bbb47c283fee1ad525e3ffb,
title = "A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are major sheddases of T cell immunoglobulin and mucin domain 3 (Tim-3)",
abstract = "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. ",
keywords = "ADAM Proteins/genetics, ADAM17 Protein, Animals, CD4-Positive T-Lymphocytes/metabolism, CD8-Positive T-Lymphocytes/metabolism, Disintegrins/metabolism, Down-Regulation, Fibroblasts/metabolism, Galectins/metabolism, Gene Expression Regulation, HEK293 Cells, Hepatitis A Virus Cellular Receptor 2, Humans, Membrane Proteins/genetics, Mice, Monocytes/metabolism, Signal Transduction, Tumor Necrosis Factor-alpha/genetics",
author = "Katja M{\"o}ller-Hackbarth and Christin Dewitz and Olga Schweigert and Ahmad Trad and Christoph Garbers and Stefan Rose-John and J{\"u}rgen Scheller",
year = "2013",
month = nov,
day = "29",
doi = "10.1074/jbc.M113.488478",
language = "English",
volume = "288",
pages = "34529--34544",
journal = "J BIOL CHEM",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "48",

}

RIS

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 -