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

Cell & Bioscience

Research

Jian Zhu¹  David Schlessinger²  Jian Sima³  Ruihan Yang³  Yuyuan Yao³ 

[1] Department of Psychology, Eastern Illinois University, 61920, Charleston, IL, USA;Laboratory of Genetics and Genomics, NIA/NIH-IRP, 251 Bayview Blvd, Room 10B014, 21224, Baltimore, MD, USA;School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, 210009, Nanjing, China;

关键词: EDA;    EDAR;    Membrane trafficking;    HED;    TNFR;   

DOI  :  10.1186/s13578-023-01082-8

 received in 2023-02-12, accepted in 2023-07-05,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundEctodysplasin-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.ResultsWe 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.ConclusionsOverall, 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.

【 授权许可】

CC BY   
© The Author(s) 2023

【 图 表 】

42004_2023_944_Article_IEq7.gif

Fig. 5

Fig. 3 (abstract A15)

40854_2023_486_Article_IEq39.gif

Fig. 1

13690_2023_1118_Article_IEq3.gif

42004_2023_939_Article_IEq5.gif