Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ‐secretase activity

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 . Synopsis The Tweak receptor Fn14 has a central role in tissue homeostasis, injury and tumors. The new study demonstrates that the protease γ‐secretase cleaves Fn14 within its transmembrane domain and controls Fn14 abundance, turnover and signaling. This study also establishes soluble, cleaved Fn14 as a biomarker for γ‐secretase activity in vivo . The cell surface receptor Fn14 is a novel, but unusually short substrate for the intramembrane protease γ‐secretase. Inhibition of γ‐secretase increases cellular and surface abundance of Fn14 and enhances it signaling in response to TWEAK ligand binding. Soluble Fn14 may serve as an easily measurable, pharmacodynamic blood biomarker for γ‐secretase activity in vitro and in vivo . Graphical Abstract The Tweak receptor Fn14 has a central role in tissue homeostasis, injury and tumors. The new study demonstrates that the protease γ‐secretase cleaves Fn14 within its transmembrane domain and controls Fn14 abundance, turnover and signaling. This study also establishes soluble, cleaved Fn14 as a biomarker for γ‐secretase activity in vivo .