Institute of Cell Biology and Immunology, University of Stuttgart, Allmandring 31, 70569, Stuttgart, Germany.
Department of Biology, Drexel University, 3245 Chestnut Street, Philadelphia, PA, 19104, USA.
Sci Rep. 2017 Jul 26;7(1):6607. doi: 10.1038/s41598-017-06993-4.
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.
肿瘤坏死因子受体 2（TNFR2）被认为介导免疫抑制和组织再生。有趣的是，肿瘤坏死因子（tmTNF）的跨膜形式对于强烈激活 TNFR2 是必要的。为了表征 TNFR2 激活过程中 tmTNF 的计量比和组成，我们构建了不同寡聚化的单链 TNF 配体（scTNF），由三个 TNF 同源结构域（THD）三聚体组成，模拟 tmTNF。使用各种细胞和体内测定方法，我们可以证明 scTNF 三聚体的更高寡聚化导致更有效的 TNF/TNFR2 聚类和随后的信号转导。重要的是，scTNF 三聚体的三维取向影响寡聚化 scTNF 配体的生物活性。我们的数据揭示了能够强烈激活 TNFR2 的 tmTNF 模拟 scTNF 配体的组织，引入了新型的 TNFR2 激动剂，有望作为治疗各种疾病的治疗药物。
