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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Autores principales: Roman Fischer, Jessica Marsal, Cristiano Guttà, Stephan A. Eisler, Nathalie Peters, John R. Bethea, Klaus Pfizenmaier, Roland E. Kontermann
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Publicado: Nature Portfolio 2017
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Acceso en línea:https://doaj.org/article/5426e79d6acc4127b9912c15e577861b
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spelling 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)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle 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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