ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

M Schulte; K Reiss; M Lettau; T Maretzky; A Ludwig; D Hartmann; B de Strooper; O Janssen; P Saftig

doi:10.1038/sj.cdd.4402101

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ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

Journal article

Open access

Peer reviewed

ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death

M Schulte, K Reiss, M Lettau, T Maretzky, A Ludwig, D Hartmann, B de Strooper, O Janssen and P Saftig

Cell death and differentiation, Vol.14(5), pp.1040-1049

05/2007

DOI: 10.1038/sj.cdd.4402101

PMID: 17290285

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https://doi.org/10.1038/sj.cdd.4402101View

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Abstract

The apoptosis-inducing Fas ligand (FasL) is a type II transmembrane protein that is involved in the downregulation of immune reactions by activation-induced cell death (AICD) as well as in T cell-mediated cytotoxicity. Proteolytic cleavage leads to the generation of membrane-bound N-terminal fragments and a soluble FasL (sFasL) ectodomain. sFasL can be detected in the serum of patients with dysregulated inflammatory diseases and is discussed to affect Fas-FasL-mediated apoptosis. Using pharmacological approaches in 293T cells, in vitro cleavage assays as well as loss and gain of function studies in murine embryonic fibroblasts (MEFs), we demonstrate that the disintegrin and metalloprotease ADAM10 is critically involved in the shedding of FasL. In primary human T cells, FasL shedding is significantly reduced after inhibition of ADAM10. The resulting elevated FasL surface expression is associated with increased killing capacity and an increase of T cells undergoing AICD. Overall, our findings suggest that ADAM10 represents an important molecular modulator of FasL-mediated cell death.

Recombinant Proteins - metabolism

Solubility - drug effects

Fas Ligand Protein - metabolism

ADAM Proteins - antagonists & inhibitors

Jurkat Cells

Humans

Enzyme Inhibitors - pharmacology

ADAM10 Protein

Protein Transport - drug effects

ADAM Proteins - metabolism

Amyloid Precursor Protein Secretases - metabolism

Animals

Fas Ligand Protein - chemistry

Membrane Proteins - antagonists & inhibitors

Protein Processing, Post-Translational - drug effects

T-Lymphocytes - cytology

T-Lymphocytes - metabolism

Membrane Proteins - metabolism

Mice

Amyloid Precursor Protein Secretases - antagonists & inhibitors

Cell Death - drug effects

Details

Title: Subtitle: ADAM10 regulates FasL cell surface expression and modulates FasL-induced cytotoxicity and activation-induced cell death
Creators: M Schulte - Biochemical Institute, Christian-Albrecht-University, Kiel, Germany
K Reiss
M Lettau
T Maretzky
A Ludwig
D Hartmann
B de Strooper
O Janssen
P Saftig
Resource Type: Journal article
Publication Details: Cell death and differentiation, Vol.14(5), pp.1040-1049
DOI: 10.1038/sj.cdd.4402101
PMID: 17290285
ISSN: 1350-9047
eISSN: 1476-5403
Language: English
Date published: 05/2007
Academic Unit: Internal Medicine
Record Identifier: 9984094406002771

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