Palmerini, V., Monzani, S., Laurichesse, Q., Loudhaief, R., Mari, S., Cecatiello, V., Olieric, V., Pasqualato, S., Colombani, J., Andersen, D.S., Mapelli, M. (2021). Drosophila TNFRs Grindelwald and Wengen bind Eiger with different affinities and promote distinct cellular functions.  Nat. Commun. 12(1): 2070.

FBrf0248618

Research paper

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.

PMC8024323 (PMC) (EuropePMC)