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Marta Llimargas | IBMB-CSIC.

An unconventional mechanism of activation for a cell receptor has been identified

A study of the Molecular Biology Institute of Barcelona (IBMB-CSIC), headquartered at the Barcelona Science Park, describes how the TNFR Wengen receptor acts during the development of  the terminal cells of the tracheal system. Knowing its basic mechanism of activation is key to better understanding the normal and pathological development of our organism. The results of the work, published in Nature Communications, open new lines of research for the treatment of multiple respiratory diseases.

There are receptors in the cell membrane that receive signals from their environment, signals that reach them through very specific molecules (ligands), which activates a cascade of intracellular signalling that regulates various events: from cell migration to their development and differentiation, or an immune response, for example.

Receptor activation regulates many of the organism’s development and self-regulation processes. Knowing how they are activated has enabled aspects of the biology of development to be understood and therapeutic targets to be identified. “Receptor activation has to be precisely controlled to trigger the right response at exactly the right time and place”, explains Marta Llimargas, who leads the Mechanisms of morphogenesis and organogenesis laboratory at IBMB-CSIC.

In theory, it is generally accepted that receptors are found in the cell membrane and that act in a similar way. But could a receptor act differently? Could it not be in the cell membrane?

This is what the work by Llimargas and her research group reveals. The team has identified an unconventional mechanism of activation in a receptor of the TNF family (Tumor Necrosis Factor), which is required for the formation of the tracheal system of the Drosophila melanogaster fly. The receptor is not found in the cell membrane, but is internalised inside the cell, “something that seems essential for activity”, the authors note.

The researchers have seen that this specific receptor, the TNFR Wengen, does not act in a conventional manner binding to its ligand and activating a conventional cascade of signalling, rather it forms a complex and directly regulates the activity of another receptor, the FGFR-Breathless. “FGFR-Breathless and TNFR Wengen are both localised in intracellular vesicles and form a complex”, reveals the researcher.

It was previously known that FGFR-Breathless is essential for the development of the trachea, and that it regulates different stages, including cell differentiation. The FGFR-Breathless receptor is localised in vesicles, but also in the cell membrane, where it receives its ligand and transduces its signal through its conventional signalling path. But nothing was known about the role of TNFR Wengen in tracheal development, according to Llimargas.

In this work the researchers show that both receptors are necessary for the same process: the differentiation of the terminal cells of the tracheal system, the cells that extend fine terminal branches that are responsible for the gas exchange once the tracheal network is functional.

Left: Terminal cells (with their nucleus marked in blue) that accumulate the FGFR-Breathless receptor in the membrane, marking the morphology of the cell, and in intracellular vesicles. The TNFR Wengen receptor (in red) accumulates in intracellular vesicles. FGFR-Breathless and TNFR Wengen colocalize in many intracellular vesicles in terminal cells (yellow). Right: Overview of the developing tracheal system in red. The TNFR Wengen receptor (in green) is detected in intracellular vesicles in the tracheal system and in cells of other tissues. Image: IBMB-CSIC.

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» Reference article: Letizia, A., Espinàs, M.L., Giannios, P. et al. The TNFR Wengen regulates the FGF pathway by an unconventional mechanism. Nat Commun14, 5874 (2023).DOI: