Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ‐secretase activity
Abstract 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 wi...
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| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2022-09-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202216084 |
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| author | Gökhan Güner Marlene Aßfalg Kai Zhao Tobias Dreyer Shibojyoti Lahiri Yun Lo Bianca Ionela Slivinschi Axel Imhof Georg Jocher Laura Strohm Christian Behrends Dieter Langosch Holger Bronger Christopher Nimsky Jörg W Bartsch Stanley R Riddell Harald Steiner Stefan F Lichtenthaler |
| author_facet | Gökhan Güner Marlene Aßfalg Kai Zhao Tobias Dreyer Shibojyoti Lahiri Yun Lo Bianca Ionela Slivinschi Axel Imhof Georg Jocher Laura Strohm Christian Behrends Dieter Langosch Holger Bronger Christopher Nimsky Jörg W Bartsch Stanley R Riddell Harald Steiner Stefan F Lichtenthaler |
| author_sort | Gökhan Güner |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-9be7449636e44c638a2a638ecfb8a4fe |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2022-09-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-9be7449636e44c638a2a638ecfb8a4fe2025-08-20T03:06:00ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842022-09-01141011710.15252/emmm.202216084Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ‐secretase activityGökhan Güner0Marlene Aßfalg1Kai Zhao2Tobias Dreyer3Shibojyoti Lahiri4Yun Lo5Bianca Ionela Slivinschi6Axel Imhof7Georg Jocher8Laura Strohm9Christian Behrends10Dieter Langosch11Holger Bronger12Christopher Nimsky13Jörg W Bartsch14Stanley R Riddell15Harald Steiner16Stefan F Lichtenthaler17German Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)Department of Neurosurgery, Philipps University MarburgDepartment of Gynecology and Obstetrics, School of Medicine, Klinikum rechts der Isar, Technical University of MunichProtein Analysis Unit, Faculty of Medicine, Biomedical Center, LMUImmunotherapy Integrated Research Center, Fred Hutchinson Cancer Research CenterGerman Center for Neurodegenerative Diseases (DZNE)Protein Analysis Unit, Faculty of Medicine, Biomedical Center, LMUGerman Center for Neurodegenerative Diseases (DZNE)Munich Cluster for Systems Neurology (SyNergy), Medical Faculty, LMUMunich Cluster for Systems Neurology (SyNergy), Medical Faculty, LMUTechnical University of MunichDepartment of Gynecology and Obstetrics, School of Medicine, Klinikum rechts der Isar, Technical University of MunichDepartment of Neurosurgery, Philipps University MarburgDepartment of Neurosurgery, Philipps University MarburgImmunotherapy Integrated Research Center, Fred Hutchinson Cancer Research CenterGerman Center for Neurodegenerative Diseases (DZNE)German Center for Neurodegenerative Diseases (DZNE)Abstract 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.https://doi.org/10.15252/emmm.202216084Alzheimer's diseaseectodomain sheddingglioblastomaintramembrane proteolysisTNR12 |
| spellingShingle | Gökhan Güner Marlene Aßfalg Kai Zhao Tobias Dreyer Shibojyoti Lahiri Yun Lo Bianca Ionela Slivinschi Axel Imhof Georg Jocher Laura Strohm Christian Behrends Dieter Langosch Holger Bronger Christopher Nimsky Jörg W Bartsch Stanley R Riddell Harald Steiner Stefan F Lichtenthaler Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ‐secretase activity EMBO Molecular Medicine Alzheimer's disease ectodomain shedding glioblastoma intramembrane proteolysis TNR12 |
| title | Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ‐secretase activity |
| title_full | Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ‐secretase activity |
| title_fullStr | Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ‐secretase activity |
| title_full_unstemmed | Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ‐secretase activity |
| title_short | Proteolytically generated soluble Tweak Receptor Fn14 is a blood biomarker for γ‐secretase activity |
| title_sort | proteolytically generated soluble tweak receptor fn14 is a blood biomarker for γ secretase activity |
| topic | Alzheimer's disease ectodomain shedding glioblastoma intramembrane proteolysis TNR12 |
| url | https://doi.org/10.15252/emmm.202216084 |
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