Novel strategies to mimic transmembrane tumor necrosis factor-dependent activation of tumor necrosis factor receptor 2
Abstract Tumor necrosis factor receptor 2 (TNFR2) is known to mediate immune suppression and tissue regeneration. Interestingly, the transmembrane form of tumor necrosis factor (tmTNF) is necessary to robustly activate TNFR2. To characterize the stoichiometry and composition of tmTNF during TNFR2 ac...
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Nature Portfolio
2017
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oai:doaj.org-article:5426e79d6acc4127b9912c15e577861b2021-12-02T12:32:57ZNovel strategies to mimic transmembrane tumor necrosis factor-dependent activation of tumor necrosis factor receptor 210.1038/s41598-017-06993-42045-2322https://doaj.org/article/5426e79d6acc4127b9912c15e577861b2017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06993-4https://doaj.org/toc/2045-2322Abstract Tumor necrosis factor receptor 2 (TNFR2) is known to mediate immune suppression and tissue regeneration. Interestingly, the transmembrane form of tumor necrosis factor (tmTNF) is necessary to robustly activate TNFR2. To characterize the stoichiometry and composition of tmTNF during TNFR2 activation, we constructed differently oligomerized single chain TNF ligands (scTNF) comprised of three TNF homology domain (THD) protomers that mimic tmTNF. Using a variety of cellular and in vivo assays, we can show that higher oligomerization of the scTNF trimers results in more efficient TNF/TNFR2 clustering and subsequent signal transduction. Importantly, the three-dimensional orientation of the scTNF trimers impacts the bioactivity of the oligomerized scTNF ligands. Our data unravel the organization of tmTNF-mimetic scTNF ligands capable of robustly activating TNFR2 and introduce novel TNFR2 agonists that hold promise as therapeutics to treat a variety of diseases.Roman FischerJessica MarsalCristiano GuttàStephan A. EislerNathalie PetersJohn R. BetheaKlaus PfizenmaierRoland E. KontermannNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-13 (2017) |
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DOAJ |
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DOAJ |
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EN |
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Medicine R Science Q |
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Medicine R Science Q Roman Fischer Jessica Marsal Cristiano Guttà Stephan A. Eisler Nathalie Peters John R. Bethea Klaus Pfizenmaier Roland E. Kontermann Novel strategies to mimic transmembrane tumor necrosis factor-dependent activation of tumor necrosis factor receptor 2 |
| description |
Abstract Tumor necrosis factor receptor 2 (TNFR2) is known to mediate immune suppression and tissue regeneration. Interestingly, the transmembrane form of tumor necrosis factor (tmTNF) is necessary to robustly activate TNFR2. To characterize the stoichiometry and composition of tmTNF during TNFR2 activation, we constructed differently oligomerized single chain TNF ligands (scTNF) comprised of three TNF homology domain (THD) protomers that mimic tmTNF. Using a variety of cellular and in vivo assays, we can show that higher oligomerization of the scTNF trimers results in more efficient TNF/TNFR2 clustering and subsequent signal transduction. Importantly, the three-dimensional orientation of the scTNF trimers impacts the bioactivity of the oligomerized scTNF ligands. Our data unravel the organization of tmTNF-mimetic scTNF ligands capable of robustly activating TNFR2 and introduce novel TNFR2 agonists that hold promise as therapeutics to treat a variety of diseases. |
| format |
article |
| author |
Roman Fischer Jessica Marsal Cristiano Guttà Stephan A. Eisler Nathalie Peters John R. Bethea Klaus Pfizenmaier Roland E. Kontermann |
| author_facet |
Roman Fischer Jessica Marsal Cristiano Guttà Stephan A. Eisler Nathalie Peters John R. Bethea Klaus Pfizenmaier Roland E. Kontermann |
| author_sort |
Roman Fischer |
| title |
Novel strategies to mimic transmembrane tumor necrosis factor-dependent activation of tumor necrosis factor receptor 2 |
| title_short |
Novel strategies to mimic transmembrane tumor necrosis factor-dependent activation of tumor necrosis factor receptor 2 |
| title_full |
Novel strategies to mimic transmembrane tumor necrosis factor-dependent activation of tumor necrosis factor receptor 2 |
| title_fullStr |
Novel strategies to mimic transmembrane tumor necrosis factor-dependent activation of tumor necrosis factor receptor 2 |
| title_full_unstemmed |
Novel strategies to mimic transmembrane tumor necrosis factor-dependent activation of tumor necrosis factor receptor 2 |
| title_sort |
novel strategies to mimic transmembrane tumor necrosis factor-dependent activation of tumor necrosis factor receptor 2 |
| publisher |
Nature Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/5426e79d6acc4127b9912c15e577861b |
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