IEO, European Institute of Oncology IRCCS, Milan, Italy.
Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen O, Denmark.
Nat Commun. 2021 Apr 6;12(1):2070. doi: 10.1038/s41467-021-22080-9.
The Drosophila tumour necrosis factor (TNF) ligand-receptor system consists of a unique ligand, Eiger (Egr), and two receptors, Grindelwald (Grnd) and Wengen (Wgn), and therefore provides a simple system for exploring the interplay between ligand and receptors, and the requirement for Grnd and Wgn in TNF/Egr-mediated processes. Here, we report the crystallographic structure of the extracellular domain (ECD) of Grnd in complex with Egr, a high-affinity hetero-hexameric assembly reminiscent of human TNF:TNFR complexes. We show that ectopic expression of Egr results in internalisation of Egr:Grnd complexes in vesicles, a step preceding and strictly required for Egr-induced apoptosis. We further demonstrate that Wgn binds Egr with much reduced affinity and is localised in intracellular vesicles that are distinct from those containing Egr:Grnd complexes. Altogether, our data provide insight into ligand-mediated activation of Grnd and suggest that distinct affinities of TNF ligands for their receptors promote different and non-redundant cellular functions.
果蝇肿瘤坏死因子（TNF）配体-受体系统由一种独特的配体 Eiger（Egr）和两个受体 Grindelwald（Grnd）和 Wengen（Wgn）组成，因此为探索配体和受体之间的相互作用以及 Grnd 和 Wgn 在 TNF/Egr 介导的过程中的要求提供了一个简单的系统。在这里，我们报告了 Grnd 的细胞外结构域（ECD）与 Egr 复合物的晶体结构，这是一种高亲和力的异六聚体组装体，类似于人类 TNF：TNFR 复合物。我们表明，Egr 的异位表达导致 Egr：Grnd 复合物在内体小泡中内化，这是 Egr 诱导凋亡之前和严格必需的步骤。我们进一步证明，Wgn 以降低的亲和力结合 Egr，并且定位于与包含 Egr：Grnd 复合物的小泡不同的细胞内小泡中。总的来说，我们的数据提供了对配体介导的 Grnd 激活的深入了解，并表明 TNF 配体对其受体的不同亲和力促进了不同且非冗余的细胞功能。
