Drosophila TNFRs Grindelwald and Wengen bind Eiger with different affinities and promote distinct cellular functions

Abstract

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.

Identification of a TNF-TNFR-like system in malaria vectors (Anopheles stephensi) likely to influence Plasmodium resistance

“…However, only grnd, but not wengen, has a predicted signal peptide signature (Supplementary Fig. 5d) N-terminal to the CRD, consistent with the localization of these two genes in Drosophila, where wengen is almost always localized in intracellular vesicles [33].…”

“…stephensi [4]. A crystal structure of the complex of eiger and its receptor from Drosophila has revealed that eiger belongs to the TNF superfamily and its two receptors, wengen and grnd, are members of the TNFR superfamily(6ZT0 [33]). A search for an active TNFR-like gene in An.…”

Yorkie ensures robust tissue growth in Drosophila ribosomal protein mutants

“…Our genetic data revealed that Egr-Grnd is essential for the induction of cell death in the yki/+, RpS3/+ wing pouch. Although the mechanism by which Egr-Grnd is activated in the mutant tissue is currently unknown, the source of Egr could be the wing disc (Igaki et al, 2009), fat body (Agrawal et al, 2016) or hemocytes (Cordero et al, 2010), and Grnd could be activated by elevated endocytosis (Igaki et al, 2009;Palmerini et al, 2021). Intriguingly, although cell death was localized to the A/P boundary in the yki/+, RpS3/+ double mutant wing pouch, adult wing defects were observed in the posterior part of the wing, suggesting some nonautonomous effect caused by local induction of massive cell death in the wing tissue.…”

RasV12; scrib−/− Tumors: A Cooperative Oncogenesis Model Fueled by Tumor/Host Interactions

“…Whether these receptors possess distinct functions within the pathway is still not clear. However, it has recently been shown that the different binding affinities of Eiger to its receptors govern their internalization trajectory within the cell, which would promote different JNK signaling outcomes [64]. This observation suggests that Wgn and Grnd might have distinct roles in the eye disc.…”