Wengen, a Tumour Necrosis Factor Receptor, regulates the Fibroblast Growth Factor pathway by an unconventional mechanism

Abstract

Unveiling the molecular mechanisms of receptor activation has led to much understanding of development as well as the identification of important drug targets. We use the Drosophila tracheal system to study the activity of two families of widely used and conserved receptors, the TNFRs and the RTK-FGFRs. Breathless, an FGFR, is known to respond to ligand by activating the differentiation program of the tracheal terminal cell. Here we show that Wengen, a TNFR, acts independently of both its canonical ligand and its downstream pathway genes to repress terminal cell differentiation. In contrast to Breathless, Wengen does not stably localise at the membrane and is instead internalised, a trafficking that seems essential for activity. We find that Wengen forms a complex with Breathless, and both colocalise in intracellular vesicles. Furthermore, Wengen regulates Breathless accumulation, likely regulating Breathless intracellular trafficking and degradation. We propose that, in the tracheal context, Wengen interacts with Breathless to regulate its activity in terminal cell differentiation. We suggest that such unconventional mechanism, involving binding by TNFRs to unrelated proteins, may be a general strategy of TNFRs activity.

The Drosophila tumor necrosis factor receptor, Wengen, couples energy expenditure with gut immunity

“…S1, B to E). The observation that the majority of Wgn is localized in intracellular vesicles rather than at the plasma membrane is consistent with our previous observations in larval epithelia and a recent study in the embryonic tracheal system (11,12). To test whether TNFR signaling regulates energy homeostasis in homeostatic conditions, we quantified lipid levels in wgn and grnd null mutant guts.…”

“…A recent study showed that Wgn localizes to late endosomes and lysosomes in the embryonic tracheal network, where it acts independently of Egr to promote degradation of the FGFR receptor, Breathless (Btl), and repress terminal cell differentiation (11). Intriguingly, the authors show that knockdown of Wgn results in the accumulation of Btl and its ligand, branchless (Bnl), in intracellular vesicles, suggesting that Wgn restricts Bnl/Btl signaling by preventing their accumulation in intracellular vesicles (11).…”

“…A recent study showed that Wgn localizes to late endosomes and lysosomes in the embryonic tracheal network, where it acts independently of Egr to promote degradation of the FGFR receptor, Breathless (Btl), and repress terminal cell differentiation (11). Intriguingly, the authors show that knockdown of Wgn results in the accumulation of Btl and its ligand, branchless (Bnl), in intracellular vesicles, suggesting that Wgn restricts Bnl/Btl signaling by preventing their accumulation in intracellular vesicles (11). The observation that Wgn suppresses signaling by restricting the accumulation of proteins in intracellular compartments in both the embryonic tracheal system and the adult gut opens up the exciting possibility that TNFRs could have a more general function in controlling protein localization and/or degradation and thereby regulate a broad spectrum of physiological processes independent of their canonical ligands.…”

DrosophilaTNF/TNFRs: At the crossroad between metabolism, immunity, and tissue homeostasis

“…While Egr employs Grnd to mediate JNK-dependent proapoptotic responses, its activation of Wgn stimulates prosurvival behaviors and cytoprotective processes to combat infections and promote tissue healing ( [15,16,50]; see below). Although the localization of Wgn in endosomes seems at odds with its function as a receptor for Egr, a fraction of Wgn is detected at the membrane upon forced expression, suggesting that it might be transiently available for ligand interaction [53]. Interestingly, in certain conditions, TNFRs are activated in ligand-independent fashions.…”

“…Hence, Wgn controls developmental photoreceptor axon targeting through its association with the ezrin/radixin/moesin (ERM) family member, moesin, a process that does not depend on Egr [52]. In addition, as discussed in more detail below, Egr-independent functions of Wgn in regulating protein stability to restrict lipid catabolism in the gut and tracheal terminal cell differentiation are starting to emerge [50,53]. Likewise, knockdown of the Avalanche (Avl), a syntaxin required for an early step of endocytosis, results in JNK-driven neoplastic overgrowth, a process that does not require Egr [10].…”