The TNFR Wengen regulates the FGF 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 t...
| Main Authors: | , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-09-01
|
| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-41549-3 |
| _version_ | 1827710266906771456 |
|---|---|
| author | Annalisa Letizia Maria Lluisa Espinàs Panagiotis Giannios Marta Llimargas |
| author_facet | Annalisa Letizia Maria Lluisa Espinàs Panagiotis Giannios Marta Llimargas |
| author_sort | Annalisa Letizia |
| collection | DOAJ |
| description | 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, 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. |
| first_indexed | 2024-03-10T17:35:40Z |
| format | Article |
| id | doaj.art-8b3aed4a5b4449fdb2e19f139a84a12d |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-03-10T17:35:40Z |
| publishDate | 2023-09-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-8b3aed4a5b4449fdb2e19f139a84a12d2023-11-20T09:51:27ZengNature PortfolioNature Communications2041-17232023-09-0114111710.1038/s41467-023-41549-3The TNFR Wengen regulates the FGF pathway by an unconventional mechanismAnnalisa Letizia0Maria Lluisa Espinàs1Panagiotis Giannios2Marta Llimargas3Department of Cells and Tissues. Institut de Biologia Molecular de Barcelona, IBMB-CSIC. Parc Científic de BarcelonaDepartment of Cells and Tissues. Institut de Biologia Molecular de Barcelona, IBMB-CSIC. Parc Científic de BarcelonaDepartment of Cells and Tissues. Institut de Biologia Molecular de Barcelona, IBMB-CSIC. Parc Científic de BarcelonaDepartment of Cells and Tissues. Institut de Biologia Molecular de Barcelona, IBMB-CSIC. Parc Científic de BarcelonaAbstract 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.https://doi.org/10.1038/s41467-023-41549-3 |
| spellingShingle | Annalisa Letizia Maria Lluisa Espinàs Panagiotis Giannios Marta Llimargas The TNFR Wengen regulates the FGF pathway by an unconventional mechanism Nature Communications |
| title | The TNFR Wengen regulates the FGF pathway by an unconventional mechanism |
| title_full | The TNFR Wengen regulates the FGF pathway by an unconventional mechanism |
| title_fullStr | The TNFR Wengen regulates the FGF pathway by an unconventional mechanism |
| title_full_unstemmed | The TNFR Wengen regulates the FGF pathway by an unconventional mechanism |
| title_short | The TNFR Wengen regulates the FGF pathway by an unconventional mechanism |
| title_sort | tnfr wengen regulates the fgf pathway by an unconventional mechanism |
| url | https://doi.org/10.1038/s41467-023-41549-3 |
| work_keys_str_mv | AT annalisaletizia thetnfrwengenregulatesthefgfpathwaybyanunconventionalmechanism AT marialluisaespinas thetnfrwengenregulatesthefgfpathwaybyanunconventionalmechanism AT panagiotisgiannios thetnfrwengenregulatesthefgfpathwaybyanunconventionalmechanism AT martallimargas thetnfrwengenregulatesthefgfpathwaybyanunconventionalmechanism AT annalisaletizia tnfrwengenregulatesthefgfpathwaybyanunconventionalmechanism AT marialluisaespinas tnfrwengenregulatesthefgfpathwaybyanunconventionalmechanism AT panagiotisgiannios tnfrwengenregulatesthefgfpathwaybyanunconventionalmechanism AT martallimargas tnfrwengenregulatesthefgfpathwaybyanunconventionalmechanism |