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.
Highlights
The tumor necrosis factor (TNF) superfamily is a family of different cytokines with various functions
Several receptors of the TNF receptor superfamily depend on a transmembrane ligand to become robustly activated
For mouse CD95L and TRAIL, soluble trimeric ligands solely containing the TNF homology domain (THD) failed to bind to their cognate receptors and were not able to activate receptor signaling
Summary
The tumor necrosis factor (TNF) superfamily is a family of different cytokines with various functions. The structural hallmark defining the TNF ligand family is the carboxy-terminal TNF homology domain (THD) which is composed of two stacked β-pleated sheets that adopt a conserved jellyroll-like tertiary fold[1,2,3] This structural composition leads to the self-association of TNF monomers into trimers and is necessary for receptor binding[1, 3]. For several members of the TNF receptor superfamily, the initial formation of ligand receptor complexes is followed by secondary multimerization into supramolecular clusters[4,5,6,7] Despite their similar trimeric organization, membrane-bound and soluble TNF ligands can differ in their activity. Of sTNF for TNFR1 is mainly caused by stabilization of ligand/receptor complexes, while transient binding of sTNF to TNFR2 results in short-lived signal incompetent complexes[15, 16]
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