TY  - JOUR
AU  - Güner, Gökhan
AU  - Assfalg, Marlene
AU  - Zhao, Kai
AU  - Dreyer, Tobias
AU  - Lahiri, Shibojyoti
AU  - Lo, Yun
AU  - Slivinschi, Bianca
AU  - Imhof, Axel
AU  - Jocher, Georg
AU  - Strohm, Laura
AU  - Behrends, Christian
AU  - Langosch, Dieter
AU  - Bronger, Holger
AU  - Nimsky, Christopher
AU  - Bartsch, Jörg W
AU  - Riddell, Stanley R
AU  - Steiner, Harald
AU  - Lichtenthaler, Stefan
TI  - Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ-secretase activity.
JO  - EMBO molecular medicine
VL  - 14
IS  - 10
SN  - 1715-4684
CY  - Heidelberg
PB  - EMBO Press
M1  - DZNE-2022-01547
SP  - e16084
PY  - 2022
N1  - CC BY: https://creativecommons.org/licenses/by/4.0/
AB  - Fn14 is a cell surface receptor with key functions in tissue homeostasis and injury but is also linked to chronic diseases. Despite its physiological and medical importance, the regulation of Fn14 signaling and turnover is only partly understood. Here, we demonstrate that Fn14 is cleaved within its transmembrane domain by the protease γ-secretase, resulting in secretion of the soluble Fn14 ectodomain (sFn14). Inhibition of γ-secretase in tumor cells reduced sFn14 secretion, increased full-length Fn14 at the cell surface, and enhanced TWEAK ligand-stimulated Fn14 signaling through the NFκB pathway, which led to enhanced release of the cytokine tumor necrosis factor. γ-Secretase-dependent sFn14 release was also detected ex vivo in primary tumor cells from glioblastoma patients, in mouse and human plasma and was strongly reduced in blood from human cancer patients dosed with a γ-secretase inhibitor prior to chimeric antigen receptor (CAR)-T-cell treatment. Taken together, our study demonstrates a novel function for γ-secretase in attenuating TWEAK/Fn14 signaling and suggests the use of sFn14 as an easily measurable pharmacodynamic biomarker to monitor γ-secretase activity in vivo.
KW  - Amyloid Precursor Protein Secretases
KW  - Animals
KW  - Biomarkers
KW  - Cytokine TWEAK
KW  - Humans
KW  - Ligands
KW  - Mice
KW  - Receptors, Cell Surface: metabolism
KW  - Receptors, Chimeric Antigen
KW  - Receptors, Tumor Necrosis Factor: metabolism
KW  - TWEAK Receptor
KW  - Tumor Necrosis Factor-alpha
KW  - Alzheimer's disease (Other)
KW  - TNR12 (Other)
KW  - ectodomain shedding (Other)
KW  - glioblastoma (Other)
KW  - intramembrane proteolysis (Other)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9549706
C6  - pmid:36069059
DO  - DOI:10.15252/emmm.202216084
UR  - https://pub.dzne.de/record/165254
ER  -