EDA ligand triggers plasma membrane trafficking of its receptor EDAR via PKA activation and SNAP23-containing complexes

Background Ectodysplasin-A (EDA), a skin-specific TNF ligand, interacts with its membrane receptor EDAR to trigger EDA signaling in skin appendage formation. Gene mutations in EDA signaling cause Anhidrotic/Hypohidrotic Ectodermal Dysplasia (A/HED), which affects the formation of skin appendages inc...

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Vydáno v:	Cell & bioscience Ročník 13; číslo 1; s. 128 - 15
Hlavní autoři:	Yao, Yuyuan, Yang, Ruihan, Zhu, Jian, Schlessinger, David, Sima, Jian
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London BioMed Central 10.07.2023 BioMed Central Ltd Springer Nature B.V BMC
Témata:	Antibodies Appendages Biomedical and Life Sciences Cell Biology Cell membranes Cells Cloning Dysplasia Ectodysplasin EDA EDAR Exocrine glands Gene expression Gene mutations Genetic aspects Glycerol HED Laboratory animals Life Sciences Ligands Membrane proteins Membrane trafficking Microbiology Mutagenesis Mutation Neurobiology Plasma Plasmids Protein purification Proteins Proteomics Signal transduction Skin Stem Cells TNFR Tumor necrosis factor China EDAR TNFR Membrane trafficking EDA HED
ISSN:	2045-3701, 2045-3701
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Shrnutí:	Background Ectodysplasin-A (EDA), a skin-specific TNF ligand, interacts with its membrane receptor EDAR to trigger EDA signaling in skin appendage formation. Gene mutations in EDA signaling cause Anhidrotic/Hypohidrotic Ectodermal Dysplasia (A/HED), which affects the formation of skin appendages including hair, teeth, and several exocrine glands. Results We report that EDA triggers the translocation of its receptor EDAR from a cytosolic compartment into the plasma membrane. We use protein affinity purification to show that upon EDA stimulation EDAR associates with SNAP23-STX6-VAMP1/2/3 vesicle trafficking complexes. We find that EDA-dependent PKA activation is critical for the association. Notably, either of two HED-linked EDAR mutations, T346M and R420W, prevents EDA-induced EDAR translocation; and both EDA-induced PKA activation and SNAP23 are required for Meibomian gland (MG) growth in a skin appendage model. Conclusions Overall, in a novel regulatory mechanism, EDA increases plasma membrane translocation of its own receptor EDAR, augmenting EDA-EDAR signaling in skin appendage formation. Our findings also provide PKA and SNAP23 as potential targets for the intervention of HED.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2045-3701 2045-3701
DOI:	10.1186/s13578-023-01082-8