Department of Cells and Tissues. Institut de Biologia Molecular de Barcelona, IBMB-CSIC. Parc Científic de Barcelona, Baldiri Reixac, 10-12, 08028, Barcelona, Spain.
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Baldiri Reixac 10, 08028, Barcelona, Spain.
Nat Commun. 2023 Sep 21;14(1):5874. doi: 10.1038/s41467-023-41549-3.
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, controls the program of differentiation of the tracheal terminal cells in response to ligand activation. Here we identify a role for Wengen, a TNFR, in repressing the terminal cell program by regulating the MAPK pathway downstream of Breathless. We find that Wengen acts independently of both its canonical ligand and downstream pathway genes. Wengen does not stably localise at the membrane and is instead internalised-a trafficking that seems essential for activity. We show that Breathless and Wengen colocalise in intracellular vesicles and form a complex. Furthermore, Wengen regulates Breathless accumulation, possibly regulating Breathless trafficking and degradation. We propose that, in the tracheal context, Wengen interacts with Breathless to regulate its activity, and suggest that such unconventional mechanism, involving binding by TNFRs to unrelated proteins, may be a general strategy of TNFRs.
揭示受体激活的分子机制不仅使我们深入了解了发育过程，还鉴定出了许多重要的药物靶点。我们利用果蝇的气管系统来研究两类广泛使用且保守的受体（TNFR 和 RTK-FGFR）的活性。Breathless 是一个 FGFR，它通过调控配体激活下游的 MAPK 通路来控制气管末端细胞的分化程序。在这里，我们发现 Wengen（一个 TNFR）通过调控 Breathless 下游的 MAPK 通路，抑制末端细胞程序，从而发挥作用。我们发现 Wengen 的作用不依赖于其典型配体和下游通路基因。Wengen 并不稳定地定位于质膜上，而是被内化，这种运输似乎对其活性是必需的。我们表明 Breathless 和 Wengen 在细胞内囊泡中共定位并形成复合物。此外，Wengen 还调控 Breathless 的积累，可能调节 Breathless 的运输和降解。我们提出，在气管中，Wengen 通过与 Breathless 相互作用来调节其活性，并推测这种涉及 TNFR 与不相关蛋白结合的非传统机制可能是 TNFR 的一种普遍策略。
