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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Published in:Cell & bioscience Vol. 13; no. 1; pp. 128 - 15
Main Authors: Yao, Yuyuan, Yang, Ruihan, Zhu, Jian, Schlessinger, David, Sima, Jian
Format: Journal Article
Language:English
Published: London BioMed Central 10.07.2023
BioMed Central Ltd
Springer Nature B.V
BMC
Subjects:
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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Summary: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.
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ISSN:2045-3701
2045-3701
DOI:10.1186/s13578-023-01082-8